The foundations of this transformation are already established in the clinic. Liposomal doxorubicin and albumin-bound paclitaxel became FDA-approved cancer therapeutics decades ago, improving tolerability and therapeutic index for patients. The decisive proof of concept, however, came with the lipid nanoparticle platforms that enabled the rapid development and global deployment of mRNA vaccines against SARS-CoV-2. According to the authors, these milestones demonstrate not only that nanomedicine works, but that nanoscale engineering can accelerate the translation of advanced therapeutics, reshape response profiles, reduce toxicity and make molecular modalities previously infeasible in vivo a practical reality.

One of the most striking frontiers described in the perspective is the use of living cells as delivery vehicles. Rather than fighting the body’s biological barriers with synthetic materials alone, researchers are now exploiting them. Nanoparticles can hitchhike on red blood cells, dramatically reducing clearance by the liver and spleen while extending circulation time, and in some designs depositing their cargo preferentially in the lungs through contact-mediated dislodging from the cell surface. Discoidal polymer particles known as cellular backpacks ride on macrophages, monocytes, T cells, neutrophils and B cells, modulating immune cell behavior in applications ranging from cancer to multiple sclerosis and traumatic brain injury. These hybrid systems combine the precision of engineered materials with the navigation skills of the body’s own cells.

Immunology is emerging as a central arena for this new generation of nanotechnologies. Cell membrane–coated nanoparticles, or CNPs, wrap synthetic cores in natural cellular membranes, presenting native antigen repertoires that conventional vaccines struggle to replicate. Cancer cell membrane–coated particles elicit potent antitumor immunity, while bacterial outer membrane vesicle platforms preserve pathogen-associated molecular patterns to generate broad-spectrum protection, including against antimicrobial-resistant strains. Nanotoxoids take this further, detaining bacterial toxins on nanoparticle surfaces so the immune system can safely learn their shapes. Advances in membrane genetic engineering and modular linker chemistry are now turning these platforms into rapidly customizable, scalable vaccine systems.

Perhaps the most futuristic concept described is the living pharmacy: implanted, encapsulated cells that continuously manufacture biologics inside the body. The recent FDA approval of Neurotech’s ENCELTO, an encapsulated allogeneic cell therapy implanted in the eye, anchors the feasibility of the approach. Modern platforms combine synthetic biology programs that control what cells produce, biomaterials that tame the foreign body response while allowing oxygen and nutrient exchange, and device interfaces offering retrievability and external control, including electro- and optogenetic actuation. Key challenges ahead include improving volumetric efficiency, ensuring predictable dosing behavior and demonstrating durable performance in large-animal models.

On the cancer front, the perspective highlights how macrophages, long viewed as obstacles that clear nanoparticles from circulation, are being reprogrammed into therapeutic partners. Ultrasound-guided platforms deliver STING agonists directly to antigen-presenting cells, while constructs that disrupt the CD47 ‘don’t eat me’ signal enable macrophage-mediated tumor cell phagocytosis. Blocking the MARCO receptor reduces hepatic sequestration of nanoparticles, boosting tumor accumulation. In hypovascularized breast cancer liver metastases, redirecting albumin-bound paclitaxel transport toward macrophages significantly improves therapeutic outcomes in a setting where conventional intravenous delivery largely fails. Implantable nanofluidic drug-eluting seeds add another layer of control, sustaining localized intratumoral immunotherapy for more than four weeks and converting immunologically cold tumors into hot ones at a fraction of the systemic dose.

Polymer chemistry is advancing carrier performance in parallel. Poly(2-oxazoline) and poly(2-oxazine) micelles achieve drug loads ten to one hundred times higher than traditional micelles, enabling intravenous formulations with minimal excipient content. The first POx-based medical product, a hemostatic sealing patch, received European approval in 2023, and the absence of preexisting anti-POx antibodies makes these polymers attractive alternatives to polyethylene glycol, which is increasingly associated with immunogenicity. Vascular-confined discoidal nanoconstructs carrying tissue plasminogen activator, meanwhile, recanalize roughly ninety percent of occluded venules in mouse models compared with about forty percent for free tPA, while preserving neurological outcomes and improving survival in stroke models.

Gene and RNA nanotherapies represent another pillar of the expanded field. In vivo CRISPR delivery via lipid nanoparticles aims to democratize access to genetic cures, bypassing the roughly 2.2 million dollar per patient cost of autologous ex vivo editing. Mesoscale nanoparticles of 300 to 500 nanometers selectively target the renal proximal tubule, delivering siRNAs and mRNAs for kidney diseases that have historically been inaccessible to systemic RNA therapeutics. In the liver, a strategy termed Repair Drive uses transient siRNA inhibition of an essential gene to eliminate unedited hepatocytes, expanding precisely corrected cells from less than one percent to approximately twenty-five percent of the liver. Transient telomerase mRNA delivered by lipid nanoparticles is showing promise for protecting skin from radiation-induced DNA damage, operating through genome and mitochondrial maintenance rather than telomere extension.

The perspective also documents a radical extension of the concept: therapeutics built from organelles and biological vesicles themselves. Extracellular vesicles from brain endothelial cells carry functional mitochondria and, when administered intravenously after stroke in mice, significantly reduce brain infarct volume and improve neurological function. Exogenous mitochondrial transfer into plaque macrophages reduces atherosclerotic burden and improves markers of fatty liver disease, positioning mitochondrial transplantation as an emerging metabolic nanotherapy. Hybrid vesicles that merge extracellular vesicle targeting with synthetic liposome stability offer enhanced tumor accumulation with improved scalability over native EV preparations.

The authors close with a vision of a modular nanomedicine ecosystem in which nanoparticles behave like cells, cells function as therapeutic devices, devices operate as immunomodulators, and imaging technologies evolve into pharmacologic tools. Realizing that vision, they emphasize, will require manufacturing and quality-by-design frameworks that embed reproducibility, safety and scalability from the outset, translating laboratory ingenuity into clinical-grade platforms capable of sensing, computing and responding to disease in real time.

Subject of Research: The expansion of nanomedicine beyond drug carriers into implantable devices, cell-based systems and living therapeutics

Article Title: Nanomedicine beyond carriers — devices, cells & living therapeutics

Article References: Grattoni, A., Paci, M. M., Arnold, N., Aryal, S., Artzi, N., Bao, G., Barcena, A. J. R., Bentov-Arava, E., Blanco, E., Chua, C. Y. X., Corradetti, B., Cryer, A. M., Decuzzi, P., De Giorgi, M., Fell, C., Gao, W., Govindaswamy, B., Jiang, W., Kara, G., … Godin, B. (2026). Nanomedicine beyond carriers — devices, cells & living therapeutics. Biomedical Microdevices, 28(3), Article 65. https://doi.org/10.1007/s10544-026-00836-8

Image Credits: AI Generated

DOI: 10.1007/s10544-026-00836-8

Keywords: nanomedicine, drug delivery, lipid nanoparticles, mRNA vaccines, cell membrane-coated nanoparticles, immunotherapy, living pharmacies, CRISPR, extracellular vesicles, mitochondrial transfer, nanofluidic implants, poly(2-oxazoline)

Nanomaterials possess unique physicochemical properties—such as tunable size, surface functionality, and the ability to respond to external stimuli—that render them ideal candidates for targeted delivery and modulation within the TME. The clinical translation of nanomedicine is already evident, with over 50 nanotherapeutic formulations approved globally. These products have not only enhanced treatment regimens for oncology but have also demonstrated efficacy in infectious diseases and neurological disorders. Exemplars in cancer therapy include Abraxane, a nanoparticle albumin-bound paclitaxel that improves drug solubility and tumor penetration, Vyxeos, which co-delivers chemotherapeutic agents for synergistic effect, and NBTXR3, a nanoparticle designed to amplify radiotherapy efficacy.

The recent comprehensive review led by Professor Kai Miao at the University of Macau offers an exhaustive examination of how nanomaterials modulate the TME to potentiate antitumor responses. This synthesis distills the multifaceted interventions of nanomedicine into four core mechanisms: enhancing drug delivery and penetration within the tumor mass, reprogramming immune suppressive elements to restore antitumor immunity, disrupting stromal barriers that impede therapeutic access, and remodeling the hypoxic and acidic metabolic niches that nurture tumor survival. The review underscores that the success of nanoplatforms hinges on their ability to precisely interact with the heterogeneous components of the TME, tailoring therapies to the fluctuating tumor milieu.

Despite these promising avenues, the transition from bench to bedside remains hindered by substantial scientific and regulatory obstacles. A critical barrier lies in the incomplete understanding of nanomaterial biotransformation and metabolism in vivo. Unlike small-molecule drugs, nanoparticles often undergo complex interactions with biological systems, including protein corona formation, immune recognition, and organ-specific distribution, which collectively influence their therapeutic activity and toxicity. Long-term safety profiles are challenging to establish given the potential for persistence or unforeseen bioaccumulation. Addressing these unknowns demands sophisticated in vivo tracking methodologies and standardized toxicological assessments that can predict human responses with greater fidelity.

The heterogeneity of the TME introduces additional complexities. Within a single tumor, variations in cell populations, extracellular matrix density, and vascularization create micro-niches that differentially affect nanoparticle delivery and efficacy. Temporal changes, driven by tumor evolution or therapy-induced remodeling, further complicate treatment. Nanomedicines must therefore be adaptable, capable of dynamic responses or combinatorial functionalities that can overcome barrier effects and mitigate resistance mechanisms. Designing smart nanoplatforms that sense and respond to environmental cues holds immense promise in this regard but requires integrative interdisciplinary collaboration.

Furthermore, a profound gap exists between fundamental nanotechnology research and clinical application. Many nanomaterials demonstrating exceptional efficacy in vitro or in animal models fail to replicate these effects in human trials. This translational gap reflects the complexity of human tumors, patient variability, and the intricacies of immune system interplay. It also points to a need for more clinically relevant preclinical models and enhanced communication between materials scientists, clinicians, and bioinformaticians. Such collaborations can refine target identification, optimize nanoplatform design, and ensure that experimental models better predict clinical outcomes.

From a regulatory perspective, the novelty of nanomedicines challenges existing frameworks. Conventional pharmaceutical evaluations often fall short in capturing the unique behaviors of nanoparticles, necessitating new paradigms in safety and efficacy assessment. Precise control over nanomaterial properties during manufacturing is critical to ensure batch-to-batch reproducibility and to meet stringent quality standards. Additionally, regulatory agencies must update guidelines to incorporate advanced characterization techniques and validate bioanalytical methods tailored for nanotherapeutics.

The 2023 Global Nanotechnology R&D Investment Analysis Report highlights a surge in funding directed towards addressing these multifactorial challenges. Leading economies have allocated billions of dollars to advance nanotechnology, recognizing its potential to transform healthcare. This financial influx is fostering cutting-edge research into responsive nanomaterials, multimodal therapeutic agents, and integrative platforms that combine diagnostics with therapy—so-called theranostics. These innovations aspire to not only treat tumors more effectively but also provide real-time feedback on therapeutic progress, allowing for adaptive treatment regimens.

Professor Miao’s review emphasizes that overcoming the hurdles associated with TME modulation necessitates holistic strategies. The complexity of cancer biology and nanomaterial science demands that clinicians contribute clinical insights and patient-derived samples; bioinformaticians perform target screening and biomarker identification; and materials scientists develop sophisticated nanoplatforms. This cross-disciplinary collaboration is pivotal in designing nanomedicines capable of precise, dynamic interaction with the TME while ensuring safety and scalability.

The translation of nanomaterials into clinically viable anticancer therapies will likely depend on iterative cycles of refinement, informed by both laboratory findings and clinical feedback. Future breakthroughs may emerge from integrating artificial intelligence and machine learning to predict nanoparticle behavior, identify optimal therapeutic windows, and tailor treatments to individual tumor profiles. Additionally, the combination of nanomedicine with emerging immunotherapies offers an exciting frontier that could synergistically enhance anticancer efficacy by overcoming immunosuppressive TME conditions.

In summary, nanomedicine offers a transformative paradigm for cancer treatment by enabling precise modulation of the TME. While significant obstacles remain—ranging from biosafety and biotransformation uncertainties to tumor heterogeneity and regulatory constraints—the accelerated investment and interdisciplinary collaboration underscore a collective commitment to overcoming these challenges. The insights presented in Professor Miao’s review illuminate pathways to bridge the translational gap, guiding the evolution of intelligent nanomaterials from promising research tools to standard components in the oncological therapeutic arsenal. The future of cancer therapy lies at this intersection of nanotechnology innovation, biological understanding, and clinical translation, promising enhanced efficacy, reduced toxicity, and ultimately improved patient outcomes.

Subject of Research: Nanomaterials and their role in modulating the tumor microenvironment for enhanced anticancer therapy

Article Title: The Future of Cancer Therapy: Nanomaterials and Tumor Microenvironment

Web References: http://dx.doi.org/10.1002/imm3.70007

Image Credits: Li Chen

Keywords: Nanotechnology, Tumor Microenvironment, Nanomedicine, Cancer Therapy, Biotransformation, Immunotherapy, Drug Delivery, Nanomaterials