Disruption of these processes is associated with inherited mitochondrial disorders and acquired diseases affecting energy-intensive organs such as the heart, brain and kidney, as well as metabolic, autoimmune and inflammatory conditions. Current mitochondrial therapeutics broadly follow three strategies: pharmacological modulation of existing mitochondria, transplantation of isolated healthy organelles and exploitation of natural intercellular mitochondrial transfer. Nanomaterials provide a common engineering platform for all three.

Their tunable size, shape and surface chemistry support hierarchical targeting from tissue to cell to organelle, while encapsulation can preserve fragile mitochondria during storage and circulation. Other designs regulate reactive oxygen species, alter energy metabolism, promote mitophagy or biogenesis, remodel inflammatory tissue environments and help mitochondrial cargo escape destructive endolysosomal pathways. Targeting mitochondria remains technically demanding because therapeutic molecules must cross the plasma membrane, escape endosomes and then traverse the outer and inner mitochondrial membranes.

Triphenylphosphonium is widely used because its cationic, lipophilic structure favors accumulation in negatively charged mitochondria, while Szeto–Schiller peptides and mitochondria-penetrating peptides exploit electrostatic and hydrophobic interactions with mitochondrial lipids. Each method has limitations: triphenylphosphonium can act as an uncoupler at concentrations above 10 micromolar, and peptides may be unstable, poorly bioavailable or rapidly degraded in circulation. Nanocarriers can conceal these liabilities, add controlled release and combine tissue- or cell-targeting ligands with organelle-localization signals.

One liposomal formulation achieved 3.7-fold greater mitochondrial accumulation than a triphenylphosphonium-based liposome and eliminated tumors in a 4T1 breast-cancer mouse model, but that finding remains an animal result rather than evidence of human efficacy. The review also describes experimental platforms for mitochondrial gene delivery and editing. Fluorinated lipid nanoparticles and mitochondrial signal sequences are being explored to reach the matrix without relying entirely on membrane potential, which can be impaired in disease.

These demonstrations establish preclinical feasibility, not a validated clinical editing method. Mitochondria can move between cells through tunneling nanotubes, gap junctions, extracellular vesicles, dendritic structures, free release and cell fusion. Such transfer can rescue stressed cells, but it can also spread dysfunctional mitochondria, alter inflammation or support tumors.

In preclinical studies, tumor-derived mitochondria carrying mutant mitochondrial DNA reduced the cytotoxic activity of tumor-infiltrating T cells, whereas mitochondrial transfer from bone marrow–derived mesenchymal stromal cells improved the metabolic fitness and antitumor response of CD8-positive T cells in animal tumor models. Nanomaterials have been used to increase connexin 43 expression, stimulate tunneling nanotubes, construct direct injection devices and engineer donor cells. A photothermal nanoblade delivered isolated mitochondria into recipient cells, while a force-controlled FluidFM system achieved targeted organelle transfer and mitochondrial-DNA propagation during subsequent cell divisions.

Transplanting isolated mitochondria offers a more immediate and controllable energy source, but the organelles rapidly lose activity outside cells, particularly under calcium-rich and oxidative conditions. Extracellular mitochondria can also act as damage-associated molecular patterns, provoking macrophage activation, neutrophil stimulation and, in animal models, increased heart-transplant rejection. Nanomaterials address some of these problems through protective vesicles, artificial membranes, metal–organic frameworks, hydrogels and microneedle patches.

In the reviewed studies, extracellular vesicles preserved mitochondrial structure and function for up to 24 hours under combined calcium and hydrogen-peroxide stress, while microvesicles retained activity for up to 72 hours. Mitochondria enclosed in ZIF-8 remained bioactive for as long as four weeks, and hydrogel or DNA-based systems extended local delivery while also scavenging reactive oxygen species. Several experimental platforms go beyond simple cargo delivery.

Engineered mitochondria have been coupled to neutrophil-hitchhiking systems for sequential targeting in myocardial ischemia–reperfusion injury and to peptides that direct them toward inflamed cardiac tissue. Other composites combine mitochondrial replacement with restoration of mitophagy: attaching healthy mitochondria to nanoparticles carrying Parkin messenger RNA increased respiratory complex I activity from 29.5% in a rotenone-damaged group to 76.5% in a mouse model of complex I deficiency. Biomimetic systems go further, using enzymes, ATP synthase and artificial proton gradients to produce ATP or NADH.

Such artificial mitochondria remain experimental substitutes rather than living organelles, but they offer a cell-free route for addressing energy deficits that has yet to be tested as a clinical treatment. The therapeutic risk can also be double-edged. Mitochondrial transfer is a normal physiological event and may be less immunogenic than transplantation, yet it is usually inefficient, difficult to direct and incompletely understood.

Pathological environments can permit indiscriminate exchange, while mesenchymal stromal cells used as donors raise separate concerns about tumor transformation and off-target differentiation. Some nanomaterials, including cobalt and silver nanoparticles, have demonstrated neurotoxic potential, and nanoplastics have been associated with senescence and cardiac aging through cGAS–STING signaling. Although clinical trials of mitochondrial transplantation are underway in conditions including myocardial infarction, ischemic stroke and inflammatory myopathy, uncertainty remains over dosing, donor–recipient metabolic compatibility, unintended genetic effects and long-term integration.

Translation will therefore require more than a sharper carrier. Future systems must be evaluated for precise tissue and organelle targeting, immune evasion, stimuli-responsive release, stability and safety, as well as reproducible manufacturing. Most of the evidence highlighted in the review comes from conventional cultures and animal models; organoids could provide more physiologically relevant assessments of efficacy and safety.

Artificial-intelligence-assisted formulation and real-time in vivo imaging are proposed as tools for optimizing these designs, but they do not substitute for long-term studies. The review’s central conclusion is promising but conditional: nanomaterials could overcome several barriers that currently restrict mitochondrial therapies, yet reliable clinical benefit will depend on integrated work across materials science, mitochondrial biology, toxicology, regulation and scalable biomanufacturing.

Subject of Research: Nanomaterial-based strategies for mitochondrial targeting, transplantation, intercellular transfer and gene delivery

Article Title: Mitochondria‐Targeted Nanotherapeutics: A Promising Strategy in Modulating Mitochondrial Function, Transfer, and Transplantation

Article References: Su, Y., Gong, Z., Mu, J., Huang, L., Yang, P., Zhang, C., Zhao, L., Yang, L., Deng, J., & Liao, X. (2026). Mitochondria‐Targeted Nanotherapeutics: A Promising Strategy in Modulating Mitochondrial Function, Transfer, and Transplantation. Advanced Science, 13(58), Article e77713. https://doi.org/10.1002/advs.77713

Image Credits: AI Generated

DOI: 10.1002/advs.77713

Keywords: mitochondrial therapy, nanomedicine, mitochondrial transplantation, intercellular transfer, nanocarriers, mitochondrial targeting, mitochondrial DNA, mitophagy, extracellular vesicles, biomimetic nanomaterials, Mitochondria, Targeted

EGFR is a receptor tyrosine kinase that sits on the cell surface and, when activated by its ligands, triggers cascades of intracellular signaling. The review’s schematic of EGFR downstream signaling illustrates the scope of its influence: pathways such as RAS–RAF–MEK–ERK and PI3K–AKT–mTOR radiate from the activated receptor, governing processes that cancer cells depend upon for proliferation, survival, migration and metastatic spread. When EGFR is overexpressed, as it frequently is in TNBC and inflammatory breast cancer, these pathways can become constitutively hyperactive, driving aggressive tumor behavior and resistance to apoptosis. On paper, this makes EGFR an obvious drug target—and indeed, EGFR inhibitors have transformed the treatment of other cancers, most notably lung carcinomas harboring activating EGFR mutations.

Yet in TNBC, the story has been far more sobering. Anti-EGFR antibodies and tyrosine kinase inhibitors, tested alone in clinical studies, have produced limited benefit. The review identifies several intertwined reasons. First, TNBC is not one disease but a constellation of molecularly distinct subtypes, and EGFR expression varies dramatically across them. Second, patient selection in past trials has often failed to stratify tumors by EGFR status or downstream pathway dependence, diluting any signal that might exist in EGFR-driven tumors. Third, cancer cells deploy an arsenal of resistance mechanisms—receptor mutations, compensatory signaling through parallel receptors, and alterations in downstream effectors—that allow tumors to circumvent a single blocked node in the network.

The subtype heterogeneity finding is particularly consequential for how future trials might be designed. According to the review, EGFR expression is highest in the basal-like 1 and 2 (BL1/2) subtypes of TNBC, followed by the mesenchymal and mesenchymal stem-like subtypes, with the immunomodulatory and luminal androgen receptor subtypes showing comparatively lower levels. This gradient matters because it implies that EGFR-directed therapy is unlikely to be a one-size-fits-all proposition. A tumor belonging to the BL1 subtype, with abundant receptor at its surface and strong signaling flux through growth-promoting pathways, may respond very differently from a luminal androgen receptor tumor in which EGFR plays a peripheral role. The practical implication is that molecular profiling—determining not just receptor abundance but the functional state of the signaling network—should precede any decision to deploy EGFR-targeted treatment.

Perhaps the most forward-looking element of the review is its case for co-targeting: pairing EGFR inhibition with simultaneous blockade of other molecules that participate in tumor progression, proliferation and metastasis. The authors analyzed transcriptomic data from EGFR-high and EGFR-low TNBC samples and identified 96 genes with substantially elevated transcription in the EGFR-high group. Among the candidates highlighted as potential co-targets are FABP4, a fatty acid binding protein implicated in metabolic adaptation; MMP9 and MMP14, matrix metalloproteinases that remodel the extracellular matrix and facilitate invasion; VCAM1, an adhesion molecule involved in metastatic trafficking; CCN4, a matricellular protein associated with tumor-stroma interactions; and CDK4/6, cell-cycle kinases whose inhibitors have already proven effective in hormone receptor-positive breast cancer.

The logic of this multi-target approach is rooted in the architecture of cellular signaling networks. A tumor cell that can reroute its survival signals through alternative pathways when EGFR is blocked becomes resistant to monotherapy. But if EGFR and a downstream or parallel node—say, CDK4/6 at the cell-cycle checkpoint, or MMP14 at the invasive front—are inhibited at the same time, the escape routes narrow dramatically. Co-targeting can also produce synergistic effects, where the combined inhibition is greater than the sum of individual effects, potentially allowing lower doses of each agent and thereby reducing the toxicity that has plagued combination regimens with conventional delivery.

This is where nanotechnology enters the picture. Delivering two or more therapeutic agents to the same tumor cells, at controlled ratios and with minimal exposure of healthy tissue, is one of pharmacology’s most stubborn challenges. Nanocarriers—including liposomes, dendrimers and other engineered nanoparticles—offer a solution that conventional formulations cannot match. Liposomes, spherical vesicles with aqueous cores surrounded by lipid bilayers, can encapsulate both hydrophilic and hydrophobic payloads. Dendrimers, highly branched synthetic macromolecules, present multiple functional groups on their surfaces for conjugating drugs, targeting ligands and imaging agents. Both platforms can be engineered to carry combinations of monoclonal antibodies, tyrosine kinase inhibitors and small interfering RNAs (siRNAs)—the last of which allows direct genetic silencing of targets such as MMP9 or FABP4 that are otherwise difficult to drug.

The advantages of nanocarrier delivery extend well beyond simple co-encapsulation. Nanoparticles can improve the pharmacokinetic profile of therapeutic agents, protecting fragile payloads such as siRNA from rapid degradation in the bloodstream and extending circulation time. Enhanced permeability and retention effects in tumor tissue, together with active targeting ligands that bind receptors on cancer cells, can increase tumor specificity and bioavailability at the disease site while sparing healthy organs. Crucially, co-loading ensures that the multiple agents arrive at the same cellular target site together, maintaining the synergistic ratios that co-targeting strategies depend upon—a level of spatial and temporal coordination that is nearly impossible to achieve with separately administered free drugs.

The review is careful to frame EGFR co-targeting as a promising direction rather than a near-term clinical reality. Appropriate molecular signatures must first be identified and rigorously validated to determine which patients will benefit, and delivery systems must demonstrate safety and efficacy in preclinical and clinical testing. The history of EGFR-targeted therapy in TNBC stands as a cautionary reminder that biological plausibility alone does not guarantee clinical success. But the integration of careful tumor classification, rational multi-target selection grounded in transcriptomic analysis, and nanocarrier-based delivery represents a coherent strategy for addressing the three failure modes—heterogeneity, poor patient selection and resistance—that have undermined earlier efforts.

For patients with aggressive EGFR-positive TNBC, the stakes could hardly be higher. If the precision framework outlined in this review matures into validated clinical protocols, the era of treating triple-negative breast cancer with blunt chemotherapy alone may give way to an approach in which a tumor’s molecular fingerprint dictates a tailored combination of inhibitors and gene-silencing agents, delivered together in a single nanoscale package. It is a vision that unites cancer genomics, network pharmacology and materials science—and one that could finally turn one of oncology’s toughest adversaries into a tractable, precisely targeted disease.

Subject of Research: EGFR co-targeting and nanocarrier-based drug delivery strategies for triple-negative breast cancer treatment

Article Title: Rethinking triple-negative breast cancer treatment through EGFR co-targeting and nanotechnology

Article References: Rethinking triple-negative breast cancer treatment through EGFR co-targeting and nanotechnology. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: triple-negative breast cancer, EGFR, co-targeting, nanocarriers, liposomes, dendrimers, siRNA, tyrosine kinase inhibitors, tumor heterogeneity, precision medicine, drug delivery, signal transduction

The review adopts what the authors call a barrier-oriented framework, following a single siRNA molecule through the sequential challenges of systemic administration. The first obstacles are extracellular. Naked siRNA is a fragile double-stranded molecule roughly 21 to 23 nucleotides long, and it is rapidly degraded by ribonucleases in blood. Chemical modification of the sugar-phosphate backbone can confer nuclease resistance, but the literature shows how narrow the margin is: studies cited in the review demonstrate that a single modification at position 14 of the guide strand, or the removal of the phosphodiester backbone in the guide’s 3′ terminal region, can abolish RISC loading and target cleavage. Stability engineering must therefore preserve the precise structural features that the RNA interference machinery recognizes, a constraint that has shaped every siRNA drug design since the first stabilized candidates entered animal models in 2005.

Even a chemically stabilized siRNA faces unfavorable pharmacokinetics. Systemically delivered RNA is cleared by the kidney and liver within minutes to hours, and it is sequestered by immune recognition pathways. The review emphasizes that double-stranded RNA is inherently immunostimulatory: Toll-like receptors and cytosolic RNA sensors can trigger interferon responses, and off-target transcript silencing through partial sequence complementarity remains a persistent safety concern. Position-specific chemical modifications can reduce off-target effects, but each design choice trades silencing potency against immune evasion, and the review notes that the elimination pathways of systemically delivered siRNA are still only partially mapped.

The most formidable extracellular barrier is the blood-brain barrier. This interface of specialized endothelial cells joined by tight junctions, basement membrane, and astrocytic endfeet excludes molecules larger than roughly 400 daltons and permits less than 2 percent of candidate central nervous system drugs to cross. Efflux transporters of the ABC family actively pump lipophilic compounds back into blood, and the glycocalyx on the luminal surface presents a further electrostatic hurdle. For siRNA, which carries a polyanionic backbone and a molecular weight near 13 kilodaltons, passive diffusion across this barrier is essentially zero. The review synthesizes evidence from nanomaterial studies showing that only engineered carriers, whether lipid nanoparticles, polymeric complexes or exosomes, achieve measurable brain transport, and even then the fraction of the injected dose reaching parenchymal neurons remains vanishingly small.

Once across the barrier, the carrier must find the right cell. The review distinguishes shared limitations from disease-specific challenges by examining evidence from Alzheimer’s, Parkinson’s and Huntington’s disease. In Alzheimer’s disease, targets include BACE1 and amyloid precursor protein, and neuron-targeted nanocomplexes have shown preclinical reductions in amyloid pathology. In Parkinson’s disease, the neuroinflammatory microenvironment dominated by activated microglia and astrocytes creates both an opportunity and a complication: ligand-functionalized lipid nanoparticles can redirect siRNA to microglia through mannose receptors or to astrocytes through adenosine conjugation, but the heterogeneity of glial states means that a carrier tuned for one disease stage may fail in another. In Huntington’s disease, antisense oligonucleotide trials targeting huntingtin expression have reached patients, providing a translational benchmark that siRNA platforms have yet to match.

The review evaluates four major nanocarrier platforms against these barriers. Lipid-based nanoparticles, the platform behind the approved RNAi drug patisiran, benefit from six decades of engineering and can incorporate ionizable lipids whose protonation in the acidic endosome drives membrane disruption. Polymeric nanocarriers, particularly poly(beta-amino ester)s, offer tunable biodegradability and bioreducible linkages that release cargo in the reducing cytosol. Engineered exosomes, the natural vesicles that cells use for intercellular communication, cross the blood-brain barrier with remarkable efficiency when surface-modified with targeting peptides such as rabies virus glycoprotein, and have shown preclinical delivery of siRNA against RIPK3 that slowed neurodegenerative progression in Alzheimer’s models. Hybrid platforms combine lipid and polymer components to balance stability, endosomal escape and controlled release, but the review notes that each additional engineering layer complicates manufacturing and regulatory characterization.

Perhaps the most stubborn intracellular barrier is endosomal entrapment. Quantitative imaging studies cited in the review show that only a small fraction of internalized siRNA escapes the endolysosomal pathway, and single-cell dose-response measurements reveal that cytosolic delivery follows a steep threshold: below a critical intracellular concentration, no gene silencing occurs regardless of how much RNA the cell has taken up. Strategies to improve escape include pH-responsive ionizable lipids, charge-invertible peptides that release siRNA in response to cytoplasmic pH, and engineered lipid phases that promote inverted hexagonal structures during endosomal acidification. Yet the review concludes that no platform has consistently achieved the combination of efficient brain transport, endosomal escape and controlled intracellular release within a single clinically scalable system.

The translational record reflects these constraints. The review highlights mivelsiran (ALN-APP), the first investigational RNAi therapeutic targeting amyloid precursor protein for Alzheimer’s disease, which has completed single and multiple ascending dose Phase 1 studies. It also notes QPI-1007, an siRNA candidate that reached Phase 2/3 for ischemic optic neuropathy, demonstrating that siRNA can reach clinical endpoints in neurological contexts when delivery is feasible. But the review is candid that preclinical mouse models rarely mimic the transcriptome of human neurodegenerative disease, and that biological heterogeneity, long-term safety, reproducibility and regulatory feasibility remain barriers that nanocarrier engineering has not resolved. Manufacturing scalability is a particular concern: microfluidic synthesis of lipid nanoparticles improves reproducibility but has not yet been validated at industrial scale for brain-targeted formulations.

The review’s conclusion is measured but pointed. Nanocarrier engineering has enhanced siRNA stability, brain targeting, intracellular trafficking and gene-silencing efficiency in preclinical models, and the field has moved from cataloguing delivery systems to understanding which barriers each platform addresses. Future progress, the authors argue, will depend on delivery systems that integrate effective brain transport, endosomal escape, controlled intracellular release and scalable manufacturing within clinical platforms, rather than optimizing any single barrier in isolation. For a field that has watched RNAi transform liver therapy while central nervous system targets remained out of reach, the message is that the silencing machinery works. What remains is the delivery problem, and it is a problem that must be solved sequentially, not piecemeal.

Subject of Research: Neuroscience

Article Title: Why does siRNA delivery still fail in neurodegenerative diseases? Biological barriers, nanocarrier engineering, and future translational directions

Article References: Erbil, G., Aykora, D., & Uzun, M. (2026). Why does siRNA delivery still fail in neurodegenerative diseases? Biological barriers, nanocarrier engineering, and future translational directions. Molecular Biology Reports, 53(1), Article 1742. https://doi.org/10.1007/s11033-026-12937-x

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12937-x

Keywords: siRNA, neurodegenerative diseases, nanocarriers, blood-brain barrier, gene silencing, drug delivery, does, delivery, still, fail, neurodegenerative, diseases

The central problem is that spinal cord injury is not a single event but a cascading catastrophe. The initial mechanical trauma triggers a wave of secondary damage: runaway inflammation, oxidative stress, programmed cell death, excitotoxicity from excessive neurotransmitter signaling, formation of a glial scar that walls off regeneration, and a hostile extracellular environment that blocks axons from regrowing. Each of these processes has become a therapeutic target in its own right, yet traditional drugs struggle to reach the injured tissue at all. The blood-spinal cord barrier, a tight cellular gatekeeper that normally protects neural tissue, also excludes most systemically administered compounds. Drugs that do get through are often cleared rapidly, suffer from short half-lives, and spread into healthy organs where they cause toxic side effects. The result has been a long string of disappointing clinical trials.

Nanocarriers promise to change that calculus by acting as programmable couriers. The review systematically compares the major delivery platforms developed over the past ten years, including liposomes, polymeric nanoparticles, micelles, inorganic nanomaterials, nanozymes, exosomes, biomimetic carriers, nanohydrogels, and composite scaffolds. Each platform occupies a distinct niche. Liposomes, spherical vesicles built from lipid bilayers, can encapsulate both water-soluble and fat-soluble drugs and shield them from premature degradation. Polymeric nanoparticles offer tunable release kinetics, allowing a therapeutic payload to be dispensed over days or weeks rather than in a single burst. Micelles, self-assembled from amphiphilic molecules, excel at solubilizing hydrophobic drugs that would otherwise be unusable. Inorganic nanomaterials bring unique physical properties, such as magnetic guidance or imaging capability, that enable simultaneous diagnosis and treatment.

Two platforms stand out in the review for their preclinical promise: biomimetic carriers and multifunctional nanozymes. Biomimetic carriers take inspiration from nature by cloaking synthetic nanoparticles in cell-derived membranes, such as those from platelets, macrophages, or stem cells. This camouflage exploits the body’s own trafficking signals, allowing the particles to cross biological barriers, evade immune clearance, and home in on inflamed tissue with far greater precision than bare synthetic particles. In the context of spinal cord injury, where the injury microenvironment is saturated with activated immune cells, such biomimetic targeting can concentrate drugs exactly where secondary damage is unfolding. Nanozymes, meanwhile, are engineered nanomaterials that mimic the catalytic activity of natural enzymes. Multifunctional nanozymes can scavenge the reactive oxygen species that drive oxidative stress while simultaneously delivering neuroprotective drugs, effectively combining a therapeutic agent and a delivery vehicle in a single construct.

The review organizes therapeutic effects around seven major mechanisms, providing a framework that researchers can use to match carrier design to pathological need. The first is inhibition of inflammation, particularly through the regulation of macrophage and microglia polarization. After injury, these immune cells can adopt pro-inflammatory states that amplify tissue destruction or anti-inflammatory states that promote repair. Nanocarriers carrying polarizing agents can push this balance toward recovery. The second mechanism is antagonism of oxidative stress, where antioxidant payloads and nanozymes neutralize the free radicals that damage neurons and oligodendrocytes in the hours and days following trauma.

The third and fourth mechanisms involve regulation of programmed cell death and neuroprotection, and the promotion of axonal regeneration alongside myelin repair. Apoptosis and related forms of controlled cell death claim many neurons that survive the initial impact, so nanocarriers that deliver anti-apoptotic agents directly to endangered cells can preserve functional circuitry. Once cell survival is secured, the challenge shifts to rebuilding connections. Axons must regrow through damaged tissue, and the myelin sheaths that insulate them must be restored for signals to travel efficiently. Nanocarriers have been used to deliver growth-promoting factors and inhibitors of myelin-associated repulsive molecules, creating a permissive environment for regeneration.

The remaining mechanisms address the structural aftermath of injury. Glial scar and extracellular matrix remodeling target the dense meshwork of proteins and glial processes that physically blocks regenerating axons; nanotherapies can soften or reorganize this barrier rather than simply trying to push axons through it. Finally, vascular repair and blood-spinal cord barrier reconstruction recognize that recovery of the injury site’s blood supply and the restoration of barrier integrity are prerequisites for lasting functional improvement. Nanocarriers delivering angiogenic factors or barrier-stabilizing compounds address this vascular dimension, which earlier therapeutic strategies often neglected.

Beyond soluble drug delivery, the review highlights biomaterials that provide physical support to the injured cord. Nanohydrogels and composite scaffolds can be injected or implanted into the lesion cavity, where they serve double duty as drug depots and as three-dimensional substrates that guide growing axons. These materials can be engineered to degrade at controlled rates, releasing their payloads in sync with the temporal phases of secondary injury, from the acute inflammatory storm to the chronic scarring stage. This stage-matched delivery is a recurring theme in the review’s analytical framework: the authors argue that rational nanomedicine design should integrate carrier characteristics with the specific pathological mechanisms dominant at each phase of injury, rather than treating spinal cord injury as a uniform target.

Despite the enthusiasm, the review is candid about the bottlenecks standing between laboratory success and clinical reality. Long-term safety validation remains insufficient for most platforms, a serious concern for materials that may persist in neural tissue. Targeting efficiency is often low, meaning that only a fraction of an administered dose reaches the injury site. Significant discrepancies between animal models and human clinical pathology complicate the interpretation of preclinical results, since rodent contusion injuries do not fully recapitulate the heterogeneity of human trauma. Scaling up nanoparticle preparation from bench-top synthesis to reproducible, pharmaceutical-grade manufacturing poses its own engineering and regulatory challenges. These hurdles explain why, despite promising preclinical data, no nanocarrier therapy for spinal cord injury has yet completed successful clinical translation.

Looking forward, the authors identify several directions that could accelerate progress. Microenvironment-responsive smart delivery systems, which release their payloads only when triggered by the acidity, enzyme activity, or oxidative conditions characteristic of injured tissue, could dramatically improve specificity and reduce side effects. The integration of nanotechnology with stem cell therapy and neuromodulation strategies could combine regenerative cell sources with precisely timed molecular support and electrical stimulation. Perhaps most importantly, the establishment of standardized evaluation systems across laboratories would make it possible to compare platforms fairly and build the robust safety and efficacy datasets that regulators require. If those pieces come together, the mechanism-driven framework laid out in this review could serve as the blueprint for turning a decade of nanocarrier innovation into the first effective treatments for a condition that medicine has long considered untreatable.

Subject of Research: Nanocarrier-based targeted drug delivery for spinal cord injury treatment

Article Title: Smart nanocarriers and biomaterials for targeted drug delivery in spinal cord injury: molecular mechanisms and translational perspectives

Article References: Han, W., Qi, P., Li, J., Min, L., Li, H., & Yin, H. (2026). Smart nanocarriers and biomaterials for targeted drug delivery in spinal cord injury: molecular mechanisms and translational perspectives. Frontiers in Bioengineering and Biotechnology, 14, Article 1973263. https://doi.org/10.3389/fbioe.2026.1973263

Image Credits: AI Generated

DOI: 10.3389/fbioe.2026.1973263

Keywords: spinal cord injury, nanocarriers, drug delivery, biomimetic carriers, nanozymes, blood-spinal cord barrier, glial scar, axonal regeneration, liposomes, exosomes, nanohydrogels, neuroprotection

The review, led by Zhifeng Wang and colleagues, maps how Panax notoginseng saponins (PNS) act on all four sequential phases of skin wound repair: haemostasis, inflammation, proliferation and remodelling. The mixture’s principal active monomers are ginsenosides Rg1 and Rb1, supported by minor components such as ginsenosides Rd and Re and notoginsenoside R1. Rather than a single blunt instrument, PNS behaves like a coordinated molecular toolkit, modulating the inflammatory microenvironment, accelerating cell proliferation and migration, driving angiogenesis and suppressing scar formation through multiple signalling pathways at once.

In the inflammatory phase, the first act of healing, moderate inflammation is useful—it clears debris and necrotic tissue—but excessive or persistent inflammation derails repair. In cell and animal studies, total PNS significantly downregulates pro-inflammatory cytokines including IL-6, IL-8 and TNF-α, reduces infiltration of neutrophils and macrophages, and helps the wound transition smoothly into the proliferative phase. The two flagship monomers divide the labour. Ginsenoside Rg1 is the core driver of pro-inflammatory suppression, targeting the NF-κB pathway and dose-dependently reducing TNF-α and IL-1β transcription. Ginsenoside Rb1 more specifically inhibits IL-6 and IL-8 and dampens mast cell degranulation, curbing histamine and tryptase release. At equivalent doses, the total saponin mixture outperforms either monomer alone, with no apparent dose-dependent toxicity—a striking illustration of multi-monomer synergy.

The molecular plumbing runs deeper still. Total PNS simultaneously targets the two central inflammatory signalling cascades: it blocks NF-κB activation by inhibiting degradation of IκBα and preventing nuclear translocation of the NF-κB p65 subunit, while also suppressing phosphorylation of ERK1/2, p38 and JNK in the MAPK pathway. Rb1 adds a layer of finesse, bidirectionally regulating p38 and JNK—inhibiting excessive JNK phosphorylation while moderately activating ERK1/2 to promote repair. Crucially, PNS also upregulates the anti-inflammatory cytokine IL-10 and pushes macrophages from the pro-inflammatory M1 phenotype toward the reparative M2 state. Rb1 is the star here, triggering M2 polarization more than three times as strongly as Rg1, upregulating M2 markers CD206 and Arg-1 and prompting M2 macrophages to secrete reparative factors such as TGF-β1 and VEGF. Yet the picture is context-dependent: in tumour models, PNS has been reported to push macrophages toward M1 instead, suggesting that the balance between Rg1 and Rb1—and the local microenvironment—dictates the outcome.

When healing shifts into the proliferative phase, PNS again shows two-pronged precision. Keratinocytes, the workhorses of re-epithelialization, are Rg1’s domain: total PNS activates the PI3K/AKT-ERK1/2 axis, pushes HaCaT keratinocytes from the G0/G1 phase into S phase, increases PCNA-positive cells and upregulates MMP-2/9 activity to clear spatial barriers to migration. Rb1, by contrast, barely touches keratinocytes but is the key regulator of fibroblasts, the cells that build granulation tissue. Through functional modulation of the TGF-β1 type II receptor, Rb1 bidirectionally governs fibroblast behaviour—promoting proliferation and collagen synthesis early, restraining excessive activation later, and maintaining the physiological 3:1 ratio of type I to type III collagen. Notably, in diabetic wound models, total PNS upregulates type III collagen more than type I, potentially deviating from that physiological ratio, hinting that other monomers exert non-specific effects that still need untangling.

Angiogenesis—the growth of new blood vessels that supply oxygen, nutrients and cytokines—is where the monomer partnership becomes most dramatic. Rg1 dose-dependently enhances VEGF expression via the HIF-1α/VEGF pathway, driving endothelial cell proliferation, migration and tube formation, and activates the PI3K/AKT pathway to raise anti-apoptotic Bcl-2 in endothelial cells. Rb1, which does not upregulate VEGF, instead boosts bFGF to promote basement membrane formation and vascular maturation, and antagonizes the VEGF overexpression caused by high-concentration Rg1—reducing risks of vascular leakage and aberrant proliferation. Total PNS also activates the JAK2-STAT3 pathway through Rb1 and inhibits platelet adhesion and aggregation to improve local circulation, with Rg1 carrying the stronger anticoagulant effect. One caveat deserves emphasis: the pro-angiogenic effect is microenvironment-dependent, significant under normoxic conditions but markedly weakened in the severely hypoxic milieu of chronic wounds—a puzzle tied to Rg1’s HIF-1α regulation that remains unresolved.

The remodelling phase, where scars are won or lost, showcases PNS’s anti-fibrotic credentials. A central mechanism of scar formation is the transition of fibroblasts into myofibroblasts, governed by the TGF-β1/Smad2/3 pathway. Total PNS blocks TGF-β1 receptor binding and inhibits Smad2/3 phosphorylation and nuclear translocation, downregulating α-SMA and easing scar hyperplasia—effects attributed mainly to Rb1. Meanwhile Rg1 fights oxidative stress, boosting activities of superoxide dismutase and glutathione peroxidase while reducing malondialdehyde accumulation, thereby protecting fibroblast and endothelial function during remodelling. In mouse models of post-traumatic scarring, topical PNS produced significantly smaller scar areas than saline controls, with improved tissue quality and no observable local adverse reactions. In human hypertrophic scar fibroblasts, PNS treatment reduced type I/III collagen synthesis, migration and α-SMA expression.

Translating these mechanisms to the bedside has demanded creative delivery engineering, because oral PNS is degraded by gastric acid and intestinal enzymes, while conventional topicals penetrate poorly and release drug unevenly. The review catalogues a new generation of carriers: PLGA nanoparticles with degradation cycles tunable from one to six months to match the healing timeline; chitosan nanoparticles offering intrinsic antibacterial, hemostatic and bioadhesive properties, though with a substantial 30%–50% burst release within 24 hours; chitosan-based hydrogels whose porous, extracellular-matrix-mimicking scaffolds support cell adhesion; thermosensitive PNIPAM hydrogels that stay liquid at room temperature and gel in situ at body temperature, releasing drug steadily for one to two weeks; and PCL electrospun fibrous membranes whose nanoscale networks resemble natural skin ECM and can be co-loaded with silver ions or antimicrobial peptides. Most futuristic of all are intelligent dressings: pH-responsive systems that release more drug as wound inflammation raises pH, and near-infrared-responsive nanofibers using graphene or gold nanoparticles to trigger pulsed, on-demand release—though the latter requires specialized equipment and raises unresolved biosafety questions.

Preclinical results across wound types are encouraging. PNS creams shortened healing time and increased tensile strength in rat incision models; PNS composite hydrogels significantly raised healing rates in diabetic foot ulcer models, improving granulation tissue regularity and regenerating hair follicles and sebaceous glands; and in superficial second-degree burns, PNS formulations upregulated PDGF-BB/PDGFR-β, accelerating granulation and epithelial repair. Early clinical exploration suggests topical PNS accelerates healing of surgical incisions and burns with favourable skin safety and no obvious irritation or allergic reactions. But the evidence hierarchy remains sobering: most mechanistic data sit at the in vitro level, animal findings form the preclinical bridge, and human evidence comes from single-centre, small-sample studies that cannot yet support high-grade clinical recommendations.

The authors are candid about the gaps. No study has yet used chemoproteomic target-deconvolution techniques such as surface plasmon resonance, microscale thermophoresis or cellular thermal shift assays to confirm the direct binding targets of PNS monomers in skin-wound systems—current evidence relies on downstream phosphorylation readouts, and several key conclusions were extrapolated from pulmonary fibrosis or oral mucosal models rather than skin. Extraction processes add another variable: ultrasonic-assisted extraction enriches Rg1 and Rb1, supercritical CO2 extraction maximizes purity but under-recovers notoginsenoside R1, and shifting Rg1:Rb1 ratios can alter—or even reverse—the direction of synergistic effects, potentially explaining contradictory results across studies. The proposed path forward pairs total PNS for full-cycle routine treatment with staged, precise monomer intervention: Rg1 for delayed epithelialization, Rb1 for high-scar-risk remodelling, and sequenced administration for diabetic ulcers. With single-cell sequencing, spatial transcriptomics, 3D bioprinted skin, dual-responsive dressings and mesenchymal stem cell co-delivery on the roadmap, this ancient saponin mixture may be moving from empirical tradition toward precision regenerative medicine—provided multicentre randomized trials and unified quality-control standards can finally catch up with the chemistry.

Subject of Research: Mechanisms and delivery systems of Panax notoginseng saponins in skin wound repair

Article Title: Application of Panax notoginseng Saponins in Skin Wound Repair: Mechanisms and Research Progress

Article References: Wang, Z., Shi, T., Tian, D., Li, R., Yao, T., Lan, J., Xi, Y., Wang, R., & Wang, J. (2026). Application of Panax notoginseng Saponins in Skin Wound Repair: Mechanisms and Research Progress. Journal of Cellular and Molecular Medicine, 30(20), Article e71381. https://doi.org/10.1111/jcmm.71381

Image Credits: AI Generated

DOI: 10.1111/jcmm.71381

Keywords: Panax notoginseng, wound healing, ginsenoside Rg1, ginsenoside Rb1, saponins, angiogenesis, scar formation, macrophage polarization, nanocarriers, hydrogels, smart dressings, diabetic foot ulcers

The central innovation rests on a pair of molecular tools called split inteins. Inteins are self-splicing protein elements that can excise themselves from a larger protein while stitching the flanking fragments back together with a peptide bond. When an intein is split into two non-functional halves — an N-terminal fragment and a C-terminal fragment — the two halves can reassociate spontaneously and reconstitute splicing activity without any external catalyst. The researchers exploited the well-characterized Npu split intein pair, fusing the N-terminal component, NpuN, to CD9, a tetraspanin membrane protein that is abundantly sorted into extracellular vesicles, and fusing the C-terminal component, NpuC, to the protein cargo of interest. The logic is elegant: because CD9 is naturally enriched on vesicle membranes, any cargo tethered to it through the reconstituted NpuN/NpuC interaction should be dragged along into the vesicle lumen or membrane during vesicle biogenesis.

What distinguishes this design from earlier intein-based loading schemes is the placement of a pH-sensitive linker between NpuC and the cargo. The researchers reasoned that this sequence would remain intact at neutral pH but would cleave under acidic conditions — precisely the environment found inside the intraluminal vesicles of producing cells and within the endosomes of recipient cells after vesicle uptake. In principle, this means the cargo is carried into vesicles while attached, then released from its membrane anchor when the vesicle interior or the recipient endosome acidifies, freeing the protein to diffuse into the cytosol and perform its function rather than remaining stuck to the vesicle membrane.

To test whether the system actually improves loading, the team fused two fluorescent reporter proteins, DsRed2 and tdTomato, to NpuC and compared engineered vesicles against vesicles loaded by passive means. The split-intein approach improved the loading of both reporters by approximately 1.3-fold relative to passive loading. That figure is modest rather than dramatic, but it represents a consistent, reproducible gain achieved with a single genetic construct and no chemical transfection reagents, electroporation, or viral envelope proteins — all of which complicate conventional loading workflows and raise safety or manufacturing concerns for clinical translation.

The most consequential demonstration, however, came when the researchers swapped the fluorescent reporters for a genuinely functional enzyme: the piggyBac transposase. This enzyme recognizes specific inverted terminal repeat sequences in DNA and excises any genetic material flanked by them, a property widely used in genome engineering. The team engineered donor cells to produce vesicles carrying NpuC-fused piggyBac transposase, isolated those vesicles, and added them to reporter cells whose genomes contained a 5′ITR–EGFP–polyadenylation signal–3′ITR cassette positioned so that its excision would switch on expression of mCherry. When the vesicles were taken up, the transposase excised the flanked cassette and the reporter cells turned red — direct evidence that a catalytically active enzyme had been loaded into vesicles, delivered across the recipient cell membrane, released into the cytosol, and had performed a genome-modifying reaction.

This functional delivery assay matters because most cargo-loading studies stop at showing that a fluorescent protein is present inside vesicles. Fluorescence can be detected without the protein being folded correctly, enzymatically competent, or accessible to the recipient cell’s cytoplasm. The piggyBac experiment closes that gap: excision of a genomic cassette is an all-or-nothing molecular event that cannot occur unless the transposase arrives intact and active. It also showcases a potential application beyond delivery for its own sake — vesicle-borne transposases could, in future work, be used to remove or rearrange specific genetic elements in living cells without exposing them to viral vectors.

A notable design choice is the deliberate avoidance of VSV-G, the vesicular stomatitis virus glycoprotein that is commonly used to pseudotype extracellular vesicles and enhance their fusion with target cell membranes. VSV-G pseudotyping improves delivery efficiency but imports a viral envelope protein into the system, which can alter vesicle tropism, trigger immune responses, and blur the line between a genuinely extracellular-vesicle-based therapy and a disguised viral vector. By building a loading and delivery system that works entirely with endogenous vesicle components — CD9 as the membrane anchor and the split intein as the molecular glue — the authors offer a platform that keeps the vesicles closer to their natural composition.

The characterization of the engineered vesicles relied on transmission electron microscopy to confirm vesicle morphology, dynamic light scattering to measure size distributions, and dot blot detection to verify the presence of the engineered mEmerald-CD9 membrane protein and the DsRed2 cargo in the vesicle fraction. These are standard and appropriate first-line techniques for confirming that the particles being studied are indeed membrane-bound vesicles of the expected size range and that the engineered constructs are physically associated with them.

The authors are candid about an important limitation: no endogenous extracellular vesicle markers or negative contamination markers were assessed in this study, which means vesicle identity and sample purity were not established by protein marker profiling. In the extracellular vesicle field, where preparations can be contaminated with protein aggregates, lipoproteins, and other non-vesicular particles, marker-based validation according to community guidelines is considered essential for attributing observed effects unambiguously to vesicles themselves. The functional piggyBac result strongly suggests that active enzyme was delivered in a membrane-associated form, but rigorous marker profiling will be needed before the platform’s mechanism of uptake and release can be stated with full confidence.

Even with those caveats, the study adds a genuinely useful tool to the extracellular vesicle engineering toolbox. The split-intein system is modular — any protein of interest can, in principle, be fused to NpuC — and it operates in a single step during natural vesicle production, avoiding post-isolation manipulation that can damage vesicles. The pH-sensitive release element adds a built-in trigger keyed to the acidic compartments that vesicles naturally encounter after uptake. If follow-up work confirms marker-defined purity, optimizes the 1.3-fold loading gain, and extends the functional delivery results to additional enzyme classes and primary cells, the approach could help extracellular vesicles move closer to their long-promised role as programmable, virus-free carriers of therapeutic proteins.

Subject of Research: Split-intein-based engineering of extracellular vesicles for protein cargo loading and functional delivery

Article Title: Split-intein-mediated engineering of VSV-G-free extracellular vesicles for enhanced cargo loading and delivery of functional proteins

Article References: Ghazi Birjandi, R., & Dehghani, H. (2026). Split-intein-mediated engineering of VSV-G-free extracellular vesicles for enhanced cargo loading and delivery of functional proteins. Scientific Reports. https://doi.org/10.1038/s41598-026-75437-9

Image Credits: AI Generated

DOI: 10.1038/s41598-026-75437-9

Keywords: extracellular vesicles, split inteins, cargo loading, CD9, tetraspanins, protein delivery, piggyBac transposase, VSV-G-free, pH-sensitive linker, nanocarriers, Scientific Reports, vesicle engineering

The commercial stakes are enormous. The global nanomedicine market was valued at 263.68 billion US dollars in 2025 and is projected to reach 759.09 billion dollars by 2034, growing at a compound annual rate of 12.83 percent, with North America holding a 46.12 percent share. Natural product-derived drugs continue to account for a significant proportion of newly approved small-molecule therapeutics, making the marriage between nanotechnology and natural chemistry one of the most consequential trends in modern drug development. By precisely tuning particle size, surface charge, and microenvironmental responsiveness, nanocarriers can cross biological barriers, boost the solubility of poorly soluble drugs, prolong retention at lesion sites, and enhance bioavailability while reducing toxicity.

Hydrogel nanocarriers represent one of the most versatile platforms described in the review. These three-dimensional crosslinked networks, held together by hydrogen bonding, pi-pi stacking, and hydrophobic effects, can transform hydrophobic herbal molecules into injectable depots. In pancreatic cancer models, a carrier-free hydrogel co-assembled from puerarin and deacetylasperulosidic acid reduced tumor cell viability to 21.39 percent, while an adenosine-gentisic acid hydrogel that targets mitochondria pushed the apoptosis rate of SW1990 cells to 33.5 percent. Smart hydrogels are also being designed to dismantle multidrug resistance by softening stiff tumor matrix, relieving hypoxia, and reactivating antitumor immunity, potentially converting drug-resistant cold tumors into therapy-sensitive hot ones.

Clinical translation of hydrogels, however, has proven difficult. OncoGel, a thermosensitive PLGA-PEG-PLGA hydrogel encapsulating paclitaxel, was tested in a phase IIb trial of 154 patients with advanced esophageal cancer. Interim safety analysis showed the intratumoral injection was well tolerated, with mostly mild local adverse reactions and no increase in systemic toxicity, yet no efficacy endpoints were ever disclosed and the product never advanced to phase III. The case illustrates a sobering gap between the safety advantages of hydrogel carriers and the demonstration of definitive benefit, compounded by low drug loading, weak intrinsic targeting, protein corona formation after systemic administration, and severe batch-to-batch variability from natural sources.

Lipid-based nanocarriers, by contrast, are the most clinically mature platform. Liposomes, solid lipid nanoparticles, and nanostructured lipid carriers exploit biomembrane-mimetic bilayers to encapsulate both hydrophilic and hydrophobic natural drugs. Preclinical successes are striking: pH-sensitive liposomes coloaded with dihydroartemisinin and tetrandrine reversed doxorubicin resistance in breast cancer by up to 46.70 percent while reducing cardiotoxicity, aptamer-modified liposomes carrying norcantharidin and paeonol achieved a 77.67 percent hepatic tumor inhibition rate, and ApoE-functionalized liposomes delivered artesunate derivatives deep into drug-resistant glioblastoma. Approved products validate the pathway: Marqibo for relapsed acute lymphoblastic leukemia, Onivyde for metastatic pancreatic cancer based on the NAPOLI-1 trial showing median overall survival of 6.1 versus 4.2 months, and the Chinese paclitaxel liposome Lipusu, which in real-world studies of advanced lung cancer combined with immunotherapy produced a median overall survival of 30.5 months.

Even liposomal curcumin has reached patients. In a phase I dose-escalation study of 32 patients with advanced solid tumors, Lipocurc established safety and tolerability, with curcumin plasma concentrations reaching 1,428 to 1,641 nanograms per milliliter at the 300 milligrams per square meter dose. Although no objective tumor responses were observed, one prostate cancer patient’s PSA fell from 649 to 355 nanograms per milliliter and a colon cancer patient’s CEA dropped from 18,542 to 6,441 micrograms per liter, providing rare clinical evidence that nanodelivery can overcome the notoriously low bioavailability of plant polyphenols. Challenges remain, including the accelerated blood clearance phenomenon after repeated PEGylated injections and limited loading capacity for poorly water-soluble drugs.

Polymeric nanocarriers form the second pillar of translation. Genexol-PM, a Cremophor-free micellar paclitaxel formulation approved in Korea, achieved a 58.5 percent overall response rate in metastatic breast cancer without routine premedication, while the micelle NK105 met safety goals in a phase III trial of 436 patients, cutting severe peripheral neuropathy from 7.5 percent to 1.4 percent compared with conventional paclitaxel, though it narrowly missed its noninferiority endpoint for progression-free survival. The camptothecin nanoparticle CRLX101 provided direct proof of tumor localization in a biopsy study, with fluorescence detectable in all post-treatment tumor samples and none in adjacent healthy tissue. Biomimetic systems add another layer of sophistication: Abraxane, the albumin-bound paclitaxel approved for breast, lung, and pancreatic cancer, exploits the endogenous gp60-SPARC transport pathway and demonstrated a 33 percent versus 19 percent response rate advantage over solvent-based paclitaxel in its pivotal trial, with far less severe neutropenia.

The review also catalogs emerging platforms with high potential but low maturity. Natural polysaccharide-derived carriers built from Astragalus, Dendrobium, and Ganoderma polysaccharides combine drug delivery with intrinsic immunomodulation, yet raw material heterogeneity makes GMP standards nearly impossible to establish. Mesoporous silica and metal-organic frameworks offer enormous surface area and drug-loading capacity, with curcumin-loaded IRMOF-16 and oridonin-loaded MOF-5 showing potent antitumor activity, but framework hydrolysis, burst release, and poorly characterized long-term toxicity keep them preclinical. Biomimetic carriers using erythrocyte membranes, exosomes, yeast cell walls, transferrin, and ferritin achieve immune evasion and homotypic targeting, but scale-up of ultrasonication and extrusion processes remains a fundamental bottleneck.

The authors argue the field is undergoing a paradigm shift from one-size-fits-all nanocarriers toward precision nanomedicines. Future priorities include multi-stimuli-responsive carriers that release payloads sequentially in response to pH, reactive oxygen species, enzymes, and temperature; integration with immunotherapy such as checkpoint blockade and CAR-T cells; genetically engineered protein cages; and artificial intelligence-driven prediction of carrier-drug interactions to screen optimal materials and process parameters. They also highlight an underappreciated frontier: nanocarriers that counteract therapy-induced toxicity, such as systems designed to neutralize the Thbs1-enriched extracellular vesicles that irradiated tumors release to damage the heart.

For now, the hierarchy of translational readiness is clear: lipid carriers lead, followed by polymeric systems and albumin technology, while hydrogels, inorganic frameworks, and polysaccharide carriers remain largely preclinical. Yet the trajectory is unmistakable. As interdisciplinary integration of materials science, biochemistry, and computational design accelerates, the therapeutic potential locked inside curcumin, berberine, paclitaxel, artemisinin, and hundreds of other natural molecules is finally being unlocked, one nanoscale vehicle at a time, promising a future where nature’s most powerful chemistry can reach the right target at the right dose with minimal harm.

Subject of Research: Nanocarrier-based delivery systems for natural drug molecules and their clinical translation

Article Title: Advanced nanocarrier delivery and therapeutic systems for natural drug molecules: mechanisms, applications, and future perspectives

Article References: Zhang, Y., Li, T., Chen, Y., & Ge, J. (2026). Advanced nanocarrier delivery and therapeutic systems for natural drug molecules: mechanisms, applications, and future perspectives. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.024

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.024

Keywords: nanocarriers, natural products, drug delivery, liposomes, hydrogels, polymeric nanoparticles, biomimetic nanocarriers, paclitaxel, curcumin, nanomedicine, clinical translation, targeted therapy

The review’s central argument is that multi-epitope vaccines are chemical products as much as immunological constructs. Once short antigenic peptide segments are stitched together with linkers, adjuvant sequences and carrier domains, the resulting molecule must survive formulation, storage, administration and biological transport. Peptide constructs frequently display unfavorable charge distribution, low aqueous solubility, excessive hydrophobicity, non-specific aggregation or susceptibility to proteases. Linkers intended to improve antigen processing can instead create new junctions, bury epitopes or introduce instability. A sequence that ranks highly in an MHC-binding predictor may therefore fail long before it reaches any immunological endpoint, and the authors insist that these chemical liabilities are part of the vaccine hypothesis itself, not a downstream inconvenience to be fixed later.

Nanocarriers enter the picture as chemically tunable systems that can partially rescue these liabilities. Polymeric nanoparticles built from poly(lactic-co-glycolic acid), chitosan or alginate offer biodegradable matrices and charge-based interactions, though they bring acidic degradation microenvironments, burst release and batch variability. Lipid-based systems, including the lipid nanoparticles that made messenger RNA vaccines possible, can encapsulate peptides and adjuvants while controlling membrane composition and PEG density, but cationic or ionizable formulations may raise reactogenicity and complement activation. Virus-like particles provide multivalent, repetitive antigen display, yet inserted epitopes can disrupt capsid assembly or reduce yield. Extracellular vesicles, a biologically derived platform, can display membrane-associated antigens and carry peptide or mRNA cargo, but they suffer from source-cell heterogeneity, variable cargo copy number and difficult purification. The review stresses that no carrier class is universally superior; performance emerges from the specific peptide-carrier-method combination.

Three primary studies cited in the review illustrate the prediction-to-formulation gap with unusual clarity. In the MS2 virus-like particle system, insertion of HIV-derived peptides into the wild-type coat protein disrupted capsid assembly entirely, and manufacturability was restored only through a single-chain dimer scaffold. In hepatitis B core virus-like particles carrying Toxoplasma gondii epitopes, four epitope combinations assembled and were immunogenic, but only one construct, HBcΔH82, improved both mouse survival and brain cyst burden, showing that display geometry rather than immunogenicity scores controlled protection. Conversely, the bioinformatically selected peptide rOmp22, a candidate against Acinetobacter baumannii, required chitosan-coated PLGA encapsulation to achieve roughly 55 percent encapsulation, sustained release and stronger protection than the free peptide. Together these cases span assembly failure, context-dependent translation and formulation rescue at distinct points of the same pipeline.

On the computational side, the authors assess the current generation of epitope predictors with measured skepticism. Tools such as NetMHCpan-4.1 and NetMHCIIpan-4.0 use neural-network ensembles trained jointly on binding-affinity and eluted-ligand data, offering broad allele coverage but weaker support for rare alleles and no direct model of T-cell receptor recognition. MHCflurry 2.0 separates affinity, antigen processing and presentation, improving mechanistic attribution for class I predictions, while BepiPred-2.0 provides scalable but conformationally limited B-cell epitope screening. Protein language models and structure-prediction systems such as AlphaFold add transferable sequence and structural representations, yet their embeddings are not calibrated vaccine endpoints and can propagate biases from training data skewed toward well-studied pathogens and common HLA alleles. Train-test leakage from homologous sequences can further inflate reported performance metrics.

The review proposes that epitope prediction be treated strictly as an upstream prioritization step, filtered through a two-stage developability gate. Candidates should first be ranked immunologically, then screened against intrinsic sequence descriptors including molecular weight, net charge, isoelectric point, hydrophobicity, aromaticity, aggregation propensity and protease-sensitive motifs. Only candidates within a predefined developability domain should proceed to context-dependent testing in the intended formulation. The authors argue that this prevents a high epitope score from overriding insolubility, aggregation or interface incompatibility, and they map each peptide liability to orthogonal analytical confirmation and explicit go or no-go decisions.

Formulation-oriented machine learning shows genuine but bounded promise. Wang and colleagues trained a LightGBM model on 325 mRNA-lipid nanoparticle formulations to predict immunoglobulin G titers and experimentally confirmed the resulting formulation ranking. Sato and colleagues used XGBoost to identify ethanol fraction, buffer pH and total flow rate as determinants of particle size and encapsulation efficiency, then applied Bayesian optimization to target lipid nanoparticles of approximately 80 and 200 nanometers. Kumar and Ardekani curated 6,454 lipid nanoparticle formulations from 21 studies and found descriptor-based ensemble models, particularly balanced random forest and extra trees classifiers, most accurate for predicting activity and cell viability. These successes, the review notes, demonstrate prediction of bounded quality attributes within a single platform, not proof that one model can optimize peptide nanovaccines across carrier classes.

Controlled release and biodistribution modeling represent the frontier where computational ambition most clearly exceeds current evidence. Classical kinetic models such as Higuchi, Korsmeyer-Peppas and Weibull remain useful but rest on assumptions that real nanocarriers strain through simultaneous diffusion, swelling, erosion, peptide-matrix binding and burst release. Physics-informed neural networks, which embed governing differential equations into neural-network training, could in principle connect sparse release data with mechanistic transport assumptions and estimate parameters that are difficult to measure directly. The authors treat this cautiously: if the governing physics is oversimplified or parameters are not identifiable, a physics-informed network can create the appearance of rigor without improving prediction. Similarly, physiologically based pharmacokinetic models borrowed from soluble small molecules cannot capture nanovaccine disposition, which involves injection-site depots, lymphatic transport, time-varying protein coronas and separate fates for carrier, intact peptide, degradation fragments and adjuvant.

The review’s conclusions are operational rather than celebratory. Future progress, the authors argue, depends less on isolated prediction accuracy than on standardized datasets, external validation, uncertainty quantification, reproducible experiments and chemically interpretable models. They propose a three-tier agenda: harmonized experimental protocols reported in FAIR-compliant formats; multiscale model integration linking release, degradation, lymphatic transport and immune timing through modular mass balances; and systematic sharing of negative data, including failed syntheses, aggregation, low loading and non-protective immune responses, which define platform boundaries and counteract publication bias. Their minimum end-to-end reporting framework requires that candidates advance only after passing predefined gates for peptide developability, interface compatibility, process robustness, intact release, pathway-specific antigen presentation and separate disposition of carrier, peptide and adjuvant, with uncertainty propagated at every stage.

The broader message for the field is a disciplined reframing of what artificial intelligence can and cannot yet do. AI has genuinely accelerated the nomination of candidate epitopes, and machine learning has delivered experimentally validated optimizations for lipid nanoparticle formulations. But the translation of predicted epitopes into chemically viable delivery systems remains the bottleneck, and it will not be solved by better binding predictors alone. The highest-impact work, Garcia-Atutxa and Villanueva-Flores conclude, will be the studies that connect immunological prediction with formulation chemistry, release kinetics, biodistribution and validation in a way transparent enough to be tested and reproduced. Until peptide solubility, aggregation, antigen orientation, corona-mediated masking and intact-antigen release are jointly represented in externally validated models, the chemical design of multi-epitope vaccine nanocarriers will remain a problem where chemistry, not computation, sets the pace.

Subject of Research: AI-supported chemical design of multi-epitope vaccine nanocarriers

Article Title: Artificial intelligence can support the chemical design of multiepitope vaccine nanocarriers

Article References: Garcia-Atutxa, I., & Villanueva-Flores, F. (2026). Artificial intelligence can support the chemical design of multiepitope vaccine nanocarriers. Discover Chemistry, 3(1), Article 469. https://doi.org/10.1007/s44371-026-00929-6

Image Credits: AI Generated

DOI: 10.1007/s44371-026-00929-6

Keywords: artificial intelligence, multi-epitope vaccines, nanocarriers, epitope prediction, peptide vaccines, lipid nanoparticles, controlled release, physics-informed neural networks, PBPK modeling, extracellular vesicles, machine learning, vaccine formulation

The review, led by Faezeh Azmoudeh and Niloofar Nazeri, followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews, known as PRISMA-ScR, to ensure a transparent and reproducible search strategy. The team queried three databases, Lens.org, PubMed, and Semantic Scholar, using combinations of search terms including nanoparticles, nanocarriers, nano-formulations, and oral candidiasis. The searches retrieved 990 records from Lens.org, 55 records from PubMed, and 141 records from Semantic Scholar. After screening for relevance to oral Candida infections and nano-enabled therapeutic applications, the researchers synthesized findings from studies spanning a broad range of nanomaterial platforms, with no restrictions on publication year. Both Candida albicans and non-albicans species were represented across the included literature, although with variable frequency, reflecting the dominant clinical role of C. albicans in oral disease.

What makes nanoparticles so attractive in the fight against oral fungi comes down to scale and mechanism. At dimensions measured in billionths of a meter, nanoparticles interact with microbial cells in ways that bulk drugs cannot. Metallic nanoparticles, for instance, can disrupt fungal cell membranes through direct physical contact, generate reactive oxygen species that inflict oxidative damage on cellular components, and interfere with essential metabolic pathways such as adenosine triphosphate production. Because these mechanisms differ fundamentally from those of conventional azole and polyene antifungals, which target ergosterol synthesis or membrane integrity through specific molecular interactions, nanoparticles can retain activity against multidrug-resistant strains that have evolved to evade traditional pharmacological attack.

The review catalogued an impressive diversity of nanomaterial platforms. Silver nanoparticles emerged as one of the most extensively studied systems, with numerous reports documenting enhanced antifungal activity and reduced minimum inhibitory concentrations against oral Candida isolates. Among the more creative approaches was the use of Zingiber officinale, or ginger, as a capping agent for silver nanoparticles, combining the antimicrobial properties of the metal with plant-derived biomolecules. Gold nanoparticles, including biosynthetically produced variants, were also evaluated, alongside titanium dioxide, copper oxide, and zinc oxide systems, the latter encompassing nano-zinc oxide and even zinc oxide quantum dots. Bismuth-based nanoparticles, including PVP-coated bismuth particles and bismuth dimercaptopropanol formulations known as BisBAL, added a less conventional but intriguing dimension to the metallic arsenal.

Beyond bare metal particles, the review highlighted the growing sophistication of functionalized and hybrid systems. Magnetic nanoparticles coated with aminosilane and conjugated with chlorhexidine, designated MNP@CHX, demonstrated the potential for externally controlled drug delivery, where an external magnetic field could guide and concentrate the therapeutic payload at the site of infection. Glucose oxidase-modified magnetic nanoparticles represented another clever design, exploiting enzymatic generation of antimicrobial species at the target site. These magnetically responsive systems, based on iron oxide cores, illustrate how nanotechnology enables not just enhanced killing but spatially targeted therapy, a particularly valuable property in the oral cavity where maintaining therapeutic concentrations of topical agents is notoriously difficult due to saliva flow and swallowing.

Lipid-based nanocarriers formed another major category in the reviewed literature. Solid lipid nanoparticles and nanostructured lipid carriers offer biocompatible matrices for encapsulating hydrophobic antifungal drugs, improving their solubility, stability, and sustained release. Fluconazole-loaded solid lipid nanoparticles were among the systems examined, as were miconazole-loaded chitosan nanoparticles, which pair a natural polysaccharide with a widely used azole drug. Chitosan itself possesses inherent antifungal and mucoadhesive properties, making it an ideal carrier material for oral applications, since it can prolong residence time on mucosal surfaces while simultaneously destabilizing fungal cell walls. Polymeric nanocarriers, including systems relevant to denture materials such as polymethyl methacrylate, extended the therapeutic concept beyond rinses and gels toward biomaterials with built-in antifungal protection.

The evidence assembled in the review consistently indicated enhanced antifungal activity for several nanoparticle systems, with reported benefits spanning direct fungal killing, mitigation of drug resistance, and improved targeted delivery within the oral environment. Studies evaluated outcomes through standard microbiological measures, including minimum inhibitory concentrations, minimum fungicidal concentrations, colony-forming unit counts, and membrane permeability assays using propidium iodide, complemented by imaging techniques such as field emission scanning electron microscopy. Both planktonic cells and biofilm states of Candida were addressed, the latter being particularly clinically relevant because biofilms on oral tissues and dental prostheses are far more resistant to antifungal agents than free-floating yeast cells.

Yet the review’s authors are careful to temper enthusiasm with a sober assessment of the field’s limitations. Heterogeneity in formulations, nanoparticle synthesis methods, dosing schemes, and outcome measures made direct comparison across studies difficult. Different research groups employed different Candida strains, different assay conditions, and different endpoints, meaning that the apparent superiority of one nanoparticle system over another often cannot be established with confidence. The variable representation of non-albicans Candida species, such as Candida glabrata and Candida krusei, which are increasingly important in clinical settings precisely because of their intrinsic resistance to common antifungals, further limits the generalizability of the accumulated evidence.

This fragmentation matters because the path from laboratory bench to dental chair is long and demanding. Before nano-enabled therapeutics can enter routine clinical use for oral candidiasis, researchers must resolve questions of safety, biocompatibility, and nanotoxicology, particularly for metallic nanoparticles whose accumulation in tissues remains a concern. Standardized testing protocols, clinically relevant infection models, and comparative head-to-head studies across Candida species are essential next steps that the review explicitly calls for. The authors emphasize that more standardized investigations, especially comparative studies across Candida species and clinically relevant models, are needed to translate the encouraging laboratory signals into evidence-based treatments.

Nevertheless, the scoping review arrives at a moment of genuine urgency in antifungal therapy. As drug-resistant Candida strains continue to spread and the immunocompromised population grows, the therapeutic pipeline desperately needs new mechanisms of action and new delivery strategies. Nano-enabled therapeutics offer both: mechanisms that circumvent conventional resistance pathways and delivery platforms that can localize potent agents precisely where they are needed. The Iranian team’s systematic mapping of the field provides researchers and clinicians with a consolidated view of what has been achieved and, just as importantly, a clear roadmap of what remains to be done. If the field can consolidate its fragmented evidence base and advance toward rigorous clinical evaluation, the tiny particles now battling Candida in laboratory dishes may one day become standard weapons against one of medicine’s most persistent oral infections.

Subject of Research: Nano-enabled therapeutic strategies for treating drug-resistant oral candidiasis

Article Title: Nano-enabled therapeutics for oral candida infections: a scoping review

Article References: Azmoudeh, F., Zarabadipour, M., Farshad, F., & Nazeri, N. (2026). Nano-enabled therapeutics for oral candida infections: a scoping review. BMC Pharmacology and Toxicology. https://doi.org/10.1186/s40360-026-01243-8

Image Credits: AI Generated

DOI: 10.1186/s40360-026-01243-8

Keywords: oral candidiasis, Candida albicans, nanoparticles, nanocarriers, antifungal resistance, silver nanoparticles, solid lipid nanoparticles, chitosan, magnetic nanoparticles, drug delivery, nanomedicine, scoping review

The construction of the nanocarrier is a three-step chemical campaign. The team began with pristine single-walled carbon nanotubes and oxidized them in a sulfuric and nitric acid mixture, sonicating and refluxing the material for 24 hours to decorate the graphitic surface with carboxyl and hydroxyl groups. These oxygenated sites served as chemical handles for the next stage: grafting branched polyethyleneimine, or PEI, a polymer rich in amine groups, using epichlorohydrin under alkaline conditions. Finally, glucuronic acid — a glucose-derived molecule — was activated with EDC and NHS coupling chemistry and conjugated to the amine-bearing scaffold. The result is a nanotube wrapped in a layered corona that is simultaneously amine-rich, hydrophilic, and decorated with sugar moieties chosen for a very specific biological reason.

That reason lies in cancer metabolism. Tumor cells are famously addicted to glucose, a phenomenon known as the Warburg effect, and they satisfy their enormous metabolic appetite by overexpressing glucose transporters on their surfaces — most notably GLUT1, which is induced by hypoxia-driven signaling and correlates with aggressive tumor behavior and poor prognosis. Glucuronic acid, as a glucose analog, is a plausible ligand for these transporters, and glucose–drug conjugates such as glufosfamide have already exploited this route to smuggle cytotoxic payloads into cancer cells. By conjugating GlcA to the nanotube surface, the researchers aimed to combine this potential targeting capability with the pH-responsive behavior that PEI naturally confers, creating a carrier whose outer layer could interact with transporter-rich tumor cells while its polymer shell responds to acidity.

Characterization confirmed that the elaborate surface chemistry had worked without destroying the underlying nanotubes. Fourier-transform infrared spectroscopy showed the disappearance of the GlcA carbonyl peak after conjugation, alongside the amide signatures of PEI grafting. X-ray diffraction revealed only minor shifts in the graphitic planes, indicating that the crystalline carbon framework remained intact beneath the organic coating. Electron microscopy told a consistent story: scanning images showed a compact polymeric layer coating the interwoven nanotube network, while transmission electron microscopy captured the preserved tubular architecture with added surface roughness from the deposited polymer. Energy-dispersive X-ray analysis quantified the transformation dramatically — carbon content fell from 90.8 to 65.6 weight percent, while oxygen rose to 30.3 percent and nitrogen appeared at 4.1 percent, the unmistakable fingerprint of an amine-rich PEI layer and oxygenated sugar residues spread uniformly across the surface.

The adsorption experiments revealed how the drug binds and what governs the process. Loading was optimal at pH 4, where 5-fluorouracil — a weakly acidic drug with a pKa of 7.93 — exists predominantly in its neutral form and the protonated PEI chains expand to expose more binding sites. Under these conditions the carrier achieved an adsorption capacity of 17.6 milligrams per gram with 88 percent loading efficiency. Kinetic analysis showed the data fit a pseudo-second-order model with correlation coefficients exceeding 0.9999, indicating that the rate is controlled by the chemistry of bond formation rather than simple diffusion. The Freundlich isotherm best described the equilibrium, pointing to adsorption on a heterogeneous surface with multilayer coverage — a picture consistent with the continuous polymeric coating seen microscopically. Notably, the modification boosted the maximum adsorption capacity more than fivefold compared with unmodified oxidized nanotubes, from 17.65 to 90.61 milligrams per gram at 298 kelvin.

Thermodynamics added a crucial layer of insight. The negative enthalpy change of −22.6 kilojoules per mole confirmed the process is exothermic, which explains why adsorption weakened at elevated temperatures, and the negative Gibbs free energy values at all tested temperatures confirmed spontaneous binding. Perhaps most interesting was the negative entropy change of −40.5 joules per mole per kelvin, indicating that drug molecules adopt a more ordered, constrained arrangement on the modified surface. The authors suggest this molecular confinement could help stabilize drug–carrier interactions under physiological conditions, limiting premature release during circulation — precisely the failure mode that makes conventional chemotherapy so toxic to healthy tissue.

The release experiments are where the design truly earns its keep. Placed in a dialysis system at 37 degrees Celsius, the drug-loaded carrier released roughly 10.5 percent of its 5-fluorouracil within the first 30 minutes at pH 5.6, versus 6.5 percent at pH 7.4. The gap widened relentlessly: 52 percent versus 34 percent after six hours, 80 percent versus 47 percent after 24 hours, and finally 88 percent versus 52 percent at the 48-hour mark. The mechanism is electrostatic. In acidic conditions, PEI amine groups become protonated, the chains repel one another and expand, and the matrix swells — loosening the network, weakening drug–carrier interactions, and opening the enlarged mesopores, which BET measurements showed had grown from 18.2 to 41.1 nanometers after functionalization. At physiological pH, reduced protonation keeps the polymer compact, trapping the drug inside a denser network.

Mathematical modeling of the release kinetics revealed a non-Fickian, or anomalous, transport mechanism. The Peppas–Sahlin equation gave the best fit with correlation coefficients of 0.999, and the diffusional exponent from the Korsmeyer–Peppas model fell between 0.5 and 1 under both pH conditions. This means release is governed not by diffusion alone but by a combination of drug diffusion through the matrix and simultaneous polymer relaxation and swelling — a dual mechanism that gives the carrier its tunable, sustained profile. The Higuchi release constant was markedly higher at acidic pH, confirming that the tumor-like environment accelerates delivery exactly when and where it matters therapeutically.

Biological testing on human colorectal cancer cells, HT-29, provided the first evidence that the chemistry translates into cellular effects. Using the MTT viability assay, the unloaded carrier showed acceptable cytocompatibility at low concentrations, with viability near untreated controls at 0.5 to 5 micrograms per milliliter, declining gradually to about 52 to 54 percent at the highest doses. The drug-loaded formulation diverged clearly from 50 micrograms per milliliter onward, reducing viability to approximately 60 percent compared with 77 percent for the bare carrier — a difference attributable to the biological activity of the delivered 5-fluorouracil. Importantly, the decline was progressive and concentration-dependent rather than abrupt, consistent with a moderated drug-availability profile rather than the sudden cytotoxic burst typical of free chemotherapeutics.

The study stops short of clinical claims, and appropriately so. The authors emphasize that further work on cellular uptake and in vivo evaluation is needed before the platform’s transporter-targeting potential and therapeutic efficacy can be established. Carbon nanotubes also carry well-known baggage — poor aqueous solubility and slow systemic clearance — that functionalization strategies like this one are designed to mitigate but not necessarily eliminate. Still, the convergence of results is compelling: a fivefold boost in drug capacity, thermodynamically stabilized binding, an 88-versus-52 percent release differential between tumor-like and physiological pH, and dose-dependent killing of colorectal cancer cells in vitro. Together they sketch a nanocarrier that loads like a sponge, travels like a locked vault, and opens like a key in the acidic lock of the tumor microenvironment — a design philosophy that may shape the next generation of stimulus-responsive cancer therapies.

Subject of Research: pH-responsive carbon nanotube-based nanocarriers for controlled delivery of the chemotherapy drug 5-fluorouracil

Article Title: Polyethyleneimine/Glucuronic acid-grafted carbon nanotubes for 5-fluorouracil delivery: adsorption optimization, pH-responsive release, and in-vitro cytotoxicity

Article References: badiee, N., Miralinaghi, P., Miralinaghi, M., & Serri, A. (2026). Polyethyleneimine/Glucuronic acid-grafted carbon nanotubes for 5-fluorouracil delivery: adsorption optimization, pH-responsive release, and in-vitro cytotoxicity. Journal of Saudi Chemical Society, 30(2), Article 15. https://doi.org/10.1007/s44442-026-00058-w

Image Credits: AI Generated

DOI: 10.1007/s44442-026-00058-w

Keywords: carbon nanotubes, drug delivery, 5-fluorouracil, polyethyleneimine, glucuronic acid, pH-responsive release, nanomedicine, chemotherapy, HT-29 cells, adsorption kinetics, cancer therapy, nanocarriers