The gelling agents used to build oleogels are diverse, and each imparts distinct properties to the resulting network. Waxes, including candelilla, beeswax, and sunflower wax, form crystalline networks whose strength and thermal behavior depend on the chain length distribution of their hydrocarbon fractions and on the cooling history of the gel. Organogelators such as ethylcellulose build networks through polymer strand aggregation, while combinations of monoglycerides, phytosterols, and other small molecules can form tubular or fibrillar structures. Because the network architecture determines how oil is trapped, how the gel flows under shear, and how it melts or softens at elevated temperature, the choice of gelling agent is effectively a choice about the final food’s behavior during processing and consumption. This is why studies that systematically link gelator chemistry to functional performance in real foods, rather than in isolated gel systems, carry particular weight for the field.

Hydrogels operate on an analogous principle in the aqueous phase, using polysaccharides and proteins to build networks that hold water, modulate viscosity, and encapsulate hydrophilic compounds. Proteins such as whey, soy, and gelatin can form gels through heat-induced unfolding and aggregation, electrostatic complexation, or enzymatic crosslinking, while polysaccharides such as alginate, pectin, and carrageenan respond to ionic strength, pH, and hydration conditions. The stimulus-responsiveness highlighted in the review literature is especially relevant here: a hydrogel that remains intact in the acidic environment of the stomach but dissociates at intestinal pH can protect a sensitive cargo through gastric transit and release it where absorption is most favorable. Similar logic applies to temperature-triggered systems, which may remain stable during refrigerated storage but soften or release their payload at physiological temperature.

Bigels represent a further step in structural sophistication because they combine two gel phases that would normally be immiscible. In a typical bigel, an oleogel phase and a hydrogel phase are brought together under shear with the help of stabilizers and interfacial design, producing a material in which hydrophilic and lipophilic compounds can be compartmentalized separately. This compartmentalization matters for several reasons. It prevents reactive ingredients from contacting one another until the moment of consumption or digestion. It allows co-encapsulation of compounds with opposing solubility requirements. And it creates release profiles that can be tuned by adjusting which phase is continuous and which is dispersed, since a compound dissolved in the continuous phase will generally diffuse out faster than one sequestered in droplets of the dispersed phase. The phase ratio, droplet size distribution, and interfacial film composition therefore become design variables that food scientists can manipulate to achieve targeted delivery behavior.

The digestive fate of these systems deserves particular attention because the gastrointestinal tract subjects ingested materials to a sequence of environments that few laboratory tests replicate faithfully. In the mouth, shear forces and amylase begin to modify the matrix. In the stomach, acidic pH, pepsin activity, and mechanical churning act on the gel structure over periods ranging from minutes to hours. In the intestine, bile salts emulsify lipids, pancreatic lipase cleaves triglycerides, and the changing pH and ionic conditions continue to remodel whatever structure remains. A gel that appears stable in a beaker may disintegrate rapidly under gastric conditions, releasing its cargo prematurely, or conversely may resist digestion so effectively that its nutrients never become bioaccessible. Static in vitro digestion protocols that sequentially simulate oral, gastric, and intestinal phases have become standard tools for probing these transformations, and more advanced dynamic models that reproduce realistic transit times, pH profiles, and shear regimes are increasingly used to refine predictions.

Scattering and microscopy techniques underpin much of the structural insight in this field. Small-angle X-ray and neutron scattering can resolve features spanning from nanometers to hundreds of nanometers, revealing crystalline packing in wax networks, polymer mesh dimensions in hydrogels, and interfacial film thickness in emulsion gels. Confocal microscopy with selective fluorescent staining can map the spatial arrangement of oil and water phases in bigels, showing whether one phase forms connected channels or isolated domains. Rheology complements these methods by measuring how the network responds to deformation, distinguishing between elastic solids that hold their shape and viscous fluids that flow. When these measurements are collected at multiple stages of digestion rather than only on the freshly prepared gel, they allow researchers to construct a mechanistic narrative connecting formulation choices to structural evolution to nutrient release, which is precisely the framing that the current literature increasingly advocates.

The application of oleogels in baked goods illustrates how laboratory findings must confront the realities of industrial processing. Cookie production involves creaming of fat and sugar, which incorporates air bubbles that later expand during baking and set the final texture. A fat that does not cream properly will yield a dense, hard cookie regardless of its nutritional profile. During baking, the structuring fat must melt or soften at the right rate to allow expansion without collapse. After baking, it contributes to texture during chewing and to the migration of moisture during storage. Replacing conventional solid fat with a wax-based oleogel therefore requires that the gel network survive creaming shear, respond appropriately to oven temperatures, and deliver acceptable sensory properties, all while carrying functional compounds such as vitamin E that may themselves be heat-sensitive. Studies demonstrating complete replacement of solid fat in a real cookie formulation, with measurements of texture, color, and nutrient retention, thus provide evidence at a level of realism that model systems cannot.

High-temperature sterilization presents an even harsher challenge for gel-based systems. Retort processing, which is used to ensure the microbiological safety of shelf-stable meat products, exposes the food to temperatures well above those of normal cooking for extended periods. Proteins denature and aggregate further, polysaccharides may degrade, water held in gel networks can be expelled as the matrix contracts, and textures can shift from desirable to rubbery or mushy. Finding natural ingredients that help gels retain water and texture through such treatment is valuable both for product quality and for reducing the need for synthetic additives. Seaweed-derived ingredients are of particular interest in this context because they bring both water-holding polysaccharides and bioactive compounds, and their use in meat systems also aligns with efforts to reformulate processed meats toward improved nutritional profiles.

Bioaccessibility, the fraction of an ingested nutrient that is released from the matrix and made available for absorption, is the metric that ultimately connects delivery system design to nutritional benefit. A bioactive compound can be chemically intact in a food yet poorly bioaccessible if it remains trapped in an indigestible network or is degraded before release. Conversely, a gel that releases its cargo too early in the digestive tract may expose it to acidic conditions that promote degradation. The design goal is therefore not simply protection or simply release, but a controlled sequence in which the matrix survives processing and storage, resists premature disruption in the stomach, and disassembles at the appropriate point in the intestine. Achieving this requires that formulation studies measure bioaccessibility directly rather than inferring it from encapsulation efficiency alone, and the growing emphasis on digestion-coupled characterization reflects this recognition.

Several methodological themes emerge from the current body of work that will likely shape future research directions. First, the value of testing gels within finished foods under realistic processing conditions is now well established, and studies that bridge the gap between model gels and commercial products will continue to be needed. Second, the combination of structural characterization across length scales with digestion experiments offers a path toward predictive understanding, in which formulation changes can be anticipated to alter release behavior without exhaustive trial and error. Third, the use of plant-derived and food-grade gelators responds to consumer and regulatory pressure, and expanding the palette of such materials, including agricultural byproducts and underexploited seaweed species, broadens the options available to formulators. Fourth, the stability of bioactive compounds during processing, storage, and digestion must be tracked alongside structural performance, since a delivery system that protects structure but not payload fails its purpose.

The broader significance of this research area lies in its potential to reconcile nutritional goals with sensory expectations. Fat reduction, sugar reduction, and nutrient fortification all tend to compromise the textures that consumers enjoy, and the failure of many reformulated products in the marketplace reflects this tension. Gels that can be tuned independently in composition, structure, and responsiveness give formulators additional degrees of freedom, allowing fat to be restructured rather than removed, water to be bound rather than lost, and nutrients to be delivered rather than degraded. As the evidence base grows to encompass more food categories, more gelator combinations, and more complete digestive characterization, these systems will move from promising laboratory concepts toward practical tools for developing foods that are simultaneously healthier, stable, and enjoyable to eat.

Subject of Research: Next-generation oleogel and hydrogel systems for food structuring, digestion, and nutrient delivery

Article Title: Editorial: Next-generation oleogel and hydrogel systems: advances in structuring, digestion, and nutrient delivery in food matrices

Article References: Castelo-Branco, V. N. (2026). Editorial: Next-generation oleogel and hydrogel systems: advances in structuring, digestion, and nutrient delivery in food matrices. Frontiers in Soft Matter, 6, Article 2013976. https://doi.org/10.3389/frsfm.2026.2013976

Image Credits: AI Generated

DOI: 10.3389/frsfm.2026.2013976

Keywords: oleogels, hydrogels, bigels, food science, nutrient delivery, digestion, soft matter, food texture, bioactive compounds, stimuli-responsive materials, Editorial, Next-generation

The conceptual framework at the heart of the review is Boolean logic, the same binary mathematics that underpins silicon computing. Inputs such as a drug, a light pulse, a metabolite or a disease-associated enzyme are treated as binary signals, and engineered circuitry combines them through operators such as AND, OR and NOT to generate a defined output, whether that is gene expression, protein release, material degradation or a therapeutic response. The review opens by cataloguing logical operators and their associated truth tables, providing a common design language for circuits built from living components. This abstraction is powerful because it allows biologists, chemists and engineers to describe, compare and compose biological information processing in the same way electrical engineers describe integrated circuits, even when the underlying hardware is a strand of RNA, a protease or a hydrogel crosslink.

Within living cells, the most mature layer of the biocomputing stack is transcriptional regulation. The field’s foundations were laid more than two decades ago with landmark constructions in Escherichia coli, including a synthetic genetic toggle switch and a repressilator, an oscillatory network of transcriptional regulators, both reported in Nature in 2000. Since then, combinatorial synthesis of genetic networks, modular AND gates that integrate environmental signals, and chimeric transcription factors built from orthogonal LacI/GalR family repressors have expanded the designer’s toolbox. In mammalian cells, large-scale design efforts have produced robust circuits with multiple inputs and outputs, and synthetic multistability has been demonstrated, allowing cells to occupy multiple stable gene-expression states. More recently, recombinase-based systems have pushed cells toward true state-machine behavior, recording event histories in DNA, and preprint work has even simulated for-loop-like counting programs in the human genome, counting to three through cascaded recombination events.

Nucleic acids themselves have emerged as an extraordinarily versatile computational medium. Engineered riboregulators enabled post-transcriptional control of gene expression as early as 2004, and higher-order RNA devices soon followed, with synthetic riboswitches processing multiple inputs inside cells. Tandem riboswitch architectures found in nature exhibit complex gene-control functions that synthetic designs have begun to emulate. The ribocomputing era arrived when complex cellular logic was demonstrated with RNA devices that integrate several sensors in a single transcript, and CRISPR-based tools such as Cas13 have added programmable RNA sensing and editing to the repertoire. Machine learning is now accelerating this design cycle dramatically: deep learning has been used to generate novel promoters in E. coli, cell-type-targeting cis-regulatory elements, ribosome binding sites, optimized untranslated regions for mRNA-delivered gene editing, and even de novo RNA aptamers predicted from structure. A 2026 study introduced Toehold-VISTA, a machine learning approach for deciphering programmable RNA sensor-target interactions, while automated platforms such as Cello 2.0 bring genuine design automation to genetic circuit engineering.

Proteins offer a faster, more compact computational layer than gene expression, and the review devotes detailed attention to protein-based biocomputability within mammalian cells. Programmable protein circuits built from modular interaction domains can process signals in minutes rather than hours, and designed protease-based signaling networks use enzymes such as tobacco etch virus protease as reversible logic elements that cleave specific peptide substrates. De novo designed protein logic gates, reported in Science in 2020, showed that computational behavior can be engineered directly into protein structures, and recent work from the DeForest group demonstrated Boolean logic-gated protein presentation through autonomously compiled molecular topology. Directed evolution platforms such as YESS and its successors have improved protease catalytic efficiency and specificity, while optogenetic tools including photocleavable proteins like PhoCl, light-inducible dimerizers, and single-component light-assisted uncaging switches give researchers exquisite spatial and temporal control. Opto-PROTACs extend this logic to targeted protein destruction, and engineered condensates provide programmable compartments where these reactions can be organized.

The review then pivots from living cells to engineered materials, a domain where the same logical principles are being embedded into synthetic and biological matter. Synthetic hydrogels have been programmed as molecular logic gates: in a 2018 Nature Chemistry study, modular biomaterial logic gates responded to combinations of environmental triggers to release therapeutics only under the correct conditions, and subsequent work extended logical stimuli-triggered delivery to small molecules and site-specifically modified proteins. Programmable polymer libraries have enabled stimuli-responsive nanocarriers containing logic gates, and AND-gated prodrug micelles have been shown to locally stimulate antitumor immunity, while Boolean logic prodrug nanoparticles support combination cancer immunotherapy. Piezoelectric enzyme systems such as MnTiO3 have been used for programmed catalysis of tumor cell death, and pH-responsive doped carbon nanodots have demonstrated multilevel, dual-readout logic operations, showing that biocomputation extends well beyond organic polymers.

DNA nanotechnology represents perhaps the most elegant materials-based computing platform. Since Nadrian Seeman’s foundational vision of nucleic acid junctions and lattices in 1982, and the synthesis of a DNA cube in 1991, researchers have folded DNA into arbitrary nanoscale shapes through DNA origami and engineered logic directly into DNA crystals. Logic-gated DNA nanorobots have been shown to transport molecular payloads to target cells, aptamer-encoded extracellular vesicles perform multi-parameter logic for colorectal cancer diagnosis, and wavelength-dependent orthogonal photoregulation enables complex DNA liberation operations. DNA circuits loaded into biomimetic ZIF-8 nanoparticles, equipped with biological amplifiers, have accurately identified specific cancers in vivo, and site-occupying interactions between DNA and metal-organic frameworks have yielded molecular sensing and logic systems. These systems translate molecular recognition directly into mechanical or chemical action, effectively making the material itself the computer.

Protein-based materials complete the materials triad. Inteins, the self-splicing protein elements, have been used to trigger artificial protein hydrogels and to assemble covalently stabilized single-chain protein nanostructures with ultra-high stability. Photocleavable proteins such as PhoCl underpin dynamic hydrogels and injectable recombinant materials like PhoCoil, which degrade on demand for minimally invasive delivery. Light-responsive ligand tethers regulate stem cell mechanics, cyclic stiffness modulation responds to user-specified stimuli, and LOVTRAP-based systems create light-responsive dynamic protein networks. Sortase-mediated functionalization, SpyTag/SpyCatcher chemistry and the broader catcher/tag toolbox allow modular, covalent assembly of protein materials, and recent work has produced biohybrid material circuits with binary decoder functionality as well as Boolean logic-based controlled release of bioactive proteins with diversified inputs. Supramolecular hydrogel-enzyme hybrids have even been taught to respond to a variety of biological substances through installed logic-gate behavior.

The most forward-looking section of the review concerns engineered living materials, where computation and matter genuinely merge. Living materials grown from engineered microbial co-cultures exhibit programmable functionalities, pattern-forming bacteria have been used to assemble pressure sensors, and de novo bacterial lifestyle programs encode entire behavioral states. Bacteria are increasingly deployed as living biosensors, including for DNA detection, and shelf-stable living materials permit continuous biosensing of oligosaccharides. Bacteriogenic protocells assembled from living material, bio-hybrid robots, and frameworks for building synthetic cells together point toward a future in which the boundary between computing substrate and living tissue dissolves. The authors also invoke the concept of collective intelligence as a unifying idea spanning scales and substrates, suggesting that the computational principles being engineered into cells and gels may illuminate how biological intelligence itself operates.

What emerges from this synthesis is a discipline in adolescence: the individual components, genetic circuits, RNA devices, protease logic, DNA nanostructures, responsive hydrogels, are mature, but their integration into robust, multiplexed, deployable systems remains the central challenge. The convergence of synthetic biology and biomaterials engineering promises applications across advanced chemical processing, additive manufacturing, tissue engineering, organ-on-chip disease modeling, and living therapeutics that sense disease markers and respond only where and when appropriate. As machine learning continues to compress design cycles and protein design tools such as ProteinMPNN improve expression, stability and function of engineered components, the vision articulated by Gharios, Ross, Li, Kottantharayil and DeForest comes into focus: a future in which computation is not confined to silicon but is woven into the living and material fabric of the world around us, executing logic wherever biology already thrives.

Subject of Research: Engineering Boolean logic-based biocomputation in living cells and stimuli-responsive biomaterials

Article Title: Engineering biocomputability in living and material systems

Article References: Gharios, R., Ross, M. L., Li, A., Kottantharayil, S. P., & DeForest, C. A. (2026). Engineering biocomputability in living and material systems. Nature Chemical Engineering. https://doi.org/10.1038/s44286-026-00433-9

Image Credits: AI Generated

DOI: 10.1038/s44286-026-00433-9

Keywords: biocomputation, synthetic biology, biomaterials, Boolean logic gates, hydrogels, DNA nanotechnology, protein circuits, genetic circuits, optogenetics, stimuli-responsive materials, engineered living materials, riboswitches

The appeal of nanocellulose begins with its feedstock. Unlike synthetic ion-exchange resins or petroleum-derived adsorbents, cellulose can be extracted from wood, cotton, agricultural residues, and even bacterial fermentation, making it renewable, inexpensive, and biodegradable. At the nanoscale, cellulose takes two dominant forms that behave very differently in water. Cellulose nanocrystals, or CNCs, are rigid rod-like crystals typically prepared by acid hydrolysis, while cellulose nanofibrils, or CNFs, are long, flexible filaments obtained through mechanical disintegration, often combined with chemical pretreatments such as TEMPO-mediated oxidation, carboxymethylation, or deep eutectic solvent processing. Both forms carry an abundance of surface hydroxyl groups, which serve as chemical handles for grafting functional ligands, and both can be tuned to carry carboxyl, amino, thiol, or other charged groups that bind metal ions with high affinity.

Conventional adsorbents, the review notes, generally suffer from limited adsorption capacity, poor recyclability, and unsustainable raw material sources. Activated carbons, clays, and chitosan derivatives have all been tried against heavy metals with varying degrees of success, but the practical record shows recurring failures at scale: adsorbents saturate quickly, regenerate incompletely, and shed fines into treated water. Hydrogels sidestep several of these problems. As swollen three-dimensional networks, they offer internal pore space where metal ions can diffuse and be captured, and their soft, water-rich structure provides an ideal matrix for embedding functional nanomaterials, from carbon dots to metal-organic frameworks to nanoparticles of zero-valent iron. Crucially, hydrogels can be cast into beads, sheets, sponges, or monoliths that are easy to handle, pack into columns, and retrieve from treated water without filtration losses.

One of the review’s most valuable contributions is its mechanistic distinction between the two families of nanocellulose hydrogels. CNC-based hydrogels achieve synergistic adsorption through the functional groups arrayed on their crystal surfaces and through the composite networks formed when nanocrystals reinforce polymer matrices such as polyacrylamide or sodium alginate. Within these networks, metal ions are captured primarily by complexation and ion exchange, mechanisms that can be quantified and optimized by adjusting the surface charge density, aspect ratio, and crosslinking chemistry of the nanocrystals. In contrast, CNF-based hydrogels exploit their continuous fiber networks: the long fibrils create interconnected channels that promote mass transport deep into the gel, while the fibril surfaces bind ions electrostatically and trap them within the pore network. This combination of electrostatic attraction and pore entrapment gives CNF gels their characteristic high uptake and rapid kinetics, particularly for cations such as Cu(II) and Pb(II).

Performance, the review shows, hinges on chemistry. Carboxymethylated cellulose nanofibrils can remove copper ions efficiently because their deprotonated carboxylate groups exchange sodium or hydrogen for dissolved metal cations. Polyethylenimine grafted onto nanocellulose through microwave-assisted synthesis has demonstrated ultra-high adsorption capacity for lead and phosphate, an amine-rich surface that chelates cations while simultaneously binding anions. For the oxyanion chromium(VI), the chemistry flips: positively charged sites are needed, so researchers have grafted poly(acryloyl hydrazide) onto cellulose nanocrystals or used poly(m-aminobenzene sulfonate)-functionalized nanofibrils, achieving excellent adsorption capacities. Thiol-modified cellulose sponges capture mercury ions through soft-soft sulfur-metal interactions, while Fe-Cu alloy coatings on nanocrystals combine lead removal with antibacterial function, a dual capability relevant to real waters that carry both chemical and microbial hazards.

Several studies highlighted in the review push the technology toward intelligence, not just capacity. Fluorescent carbon dots incorporated into cellulose nanofibril and chitosan hydrogels allow simultaneous sensing and scavenging, so the same material that removes Cu(II) and Cr(VI) signals its progress optically, enabling operators to monitor saturation in real time. Stimuli-responsive designs add another layer: pH-responsive nanocellulose/alginate/metal-organic framework hydrogels can regulate ion uptake with changes in acidity, opening possibilities for triggered regeneration or controlled release. Mechanical durability, long the Achilles’ heel of hydrogel adsorbents, has been addressed through double-network architectures, ion-induced crosslinking with cations such as zinc, and physically crosslinked, self-healing composites of polyacrylamide and cellulose nanofibers that survive repeated deformation during column operation.

Cost and sustainability, the review emphasizes, are as decisive as performance. Low-cost production routes using agricultural waste feedstocks, including rice husk, banana rachis, sugarcane bagasse, barley straw, ramie fibers, garlic and agave waste, and licorice residue, demonstrate that nanocellulose adsorbents can be sourced from materials that would otherwise be burned or landfilled. Ball milling, mechanochemical processing, deep eutectic solvents, formic acid and choline chloride pretreatments, and Fenton-based oxidation have all been deployed to liberate nanocellulose from these matrices with reduced energy and chemical inputs compared with traditional sulfuric acid hydrolysis and intensive homogenization. Studies that tracked the economics of dicarboxylic nanocellulose for copper removal report competitive costs against commercial alternatives, suggesting that sustainability here need not come at a premium.

Real-world validation is beginning to appear. Nanocellulose/alginate composite beads modified in situ have been tested for purifying mining effluents, one of the harshest chemical environments any adsorbent can face, and porous sodium alginate/cellulose nanofiber microspheres have been evaluated in wastewater matrices rather than clean laboratory solutions. Rice husk-derived nanocellulose scaffolds have shown highly efficient removal of heavy metal ions from contaminated water, and nitro-oxidized nanofibrils from banana rachis have delivered both effective lead removal and strong structural films. Yet the review is blunt about the remaining gaps. Scalable, low-cost preparation remains an obstacle: many laboratory protocols rely on exotic reagents, long reaction times, or energy-intensive homogenization that would be difficult to reproduce at a treatment plant. Antifouling performance in complex water matrices is another unresolved challenge, since organic matter, oils, and microbial biofilms compete for surface area and can poison binding sites far faster than heavy metals arrive.

The authors close by sketching a roadmap for engineering translation. Future development, they argue, should prioritize functional designs that combine adsorption with detection and self-reporting, architectures that resist fouling in chemically complex effluents, and manufacturing processes validated on waste-derived feedstocks at industrially relevant scales. If those goals are met, nanocellulose hydrogels could shift heavy metal remediation away from energy-hungry precipitation and membrane processes and toward a quieter, greener model: materials grown from plants, deployed as soft three-dimensional networks, and returned harmlessly to the biosphere when spent. For a world in which four decades of sediment records show heavy metal contamination resurging even in highly regulated coastal waters, the prospect of a renewable adsorbent that captures lead from water and can be built from rice husks is more than a laboratory curiosity. It is a plausible piece of the global water security puzzle, and the detailed mechanistic understanding assembled in this review brings the field measurably closer to the day when that piece can be put into service.

Subject of Research: Nanocellulose-based hydrogels for heavy metal removal from contaminated water

Article Title: Review: nanocellulose-based hydrogels for heavy metal removal from water

Article References: Zuo, R., Wu, S., Sun, D., & Liu, Y. (2026). Review: nanocellulose-based hydrogels for heavy metal removal from water. Journal of Materials Science. https://doi.org/10.1007/s10853-026-13763-z

Image Credits: AI Generated

DOI: 10.1007/s10853-026-13763-z

Keywords: nanocellulose, hydrogels, cellulose nanocrystals, cellulose nanofibrils, heavy metal removal, water treatment, adsorption, agricultural waste, green adsorbents, wastewater remediation, stimuli-responsive materials, pollution

The motivation for the review stems from well-documented shortcomings in the current generation of delivery platforms. Lipid nanoparticles, which rose to global prominence through mRNA vaccines, offer good biocompatibility and high transfection efficiency but are rapidly cleared by the reticuloendothelial system, limiting their targeting capability. Polymeric carriers such as PLGA allow controlled degradation rates yet frequently suffer from burst release, making sustained, stable dosing difficult. Inorganic nanocarriers like mesoporous silica nanoparticles achieve high drug loading and stability but degrade poorly, raising long-term toxicity concerns. Biologically derived systems such as exosomes possess natural targeting properties and low immunogenicity, but their complex extraction, purification and low production yields hinder large-scale use. Beyond these material-specific flaws, the authors note that existing platforms still struggle with targeting recognition, circulation stability, cellular uptake and tissue penetration, particularly against the hostile and heterogeneous terrain of solid tumors.

What distinguishes assembly-based delivery is the way it exploits weak intermolecular forces—hydrogen bonding, electrostatic interactions, pi-pi stacking, van der Waals forces and hydrophobic effects—as programmable design tools rather than incidental chemistry. The review organizes the field’s construction principles into four synergistic mechanisms. Thermodynamic driving promotes the spontaneous formation of ordered structures as systems minimize free energy, with entropy-driven strategies such as evaporation-induced self-assembly producing long-range ordered films and hydrophobic effects combined with DNA origami achieving sub-nanometer positioning precision. Molecular recognition imparts specificity through DNA base pairing, antigen-antibody binding, host-guest chemistry and metal-ligand coordination, the latter enabling precise synthesis of porous frameworks such as metal-organic frameworks and covalent organic frameworks.

The remaining two mechanisms push self-assembly beyond static equilibrium. External regulation introduces electric, optical, magnetic and thermal fields, or chemical perturbations of pH, ionic strength and solvent polarity, to steer assembly pathways and enable reversible structural reconfiguration. The authors highlight pH-responsive supramolecular polymers that assemble and disassemble within milliseconds, ideal for rapid sensing, as well as magnetic fields that guide iron oxide nanoparticles into ordered arrangements for adaptive optical components. Kinetic control, the fourth mechanism, deliberately manipulates energy-evolution pathways and intermediate states rather than settling for thermodynamically stable end products. Perhaps most strikingly, the review describes how deep learning models such as AlphaFold2, originally built for protein structure prediction, are now being extended to the rational design of self-assembling peptide sequences, dramatically shortening high-throughput screening cycles and revealing kinetic assembly pathways previously inaccessible to conventional methods.

The building blocks available to designers are equally diverse. Peptides and proteins remain cornerstone materials: peptide nanofibers serve as carriers for synergistic tumor chemotherapy, stimuli-responsive peptide hydrogels support cartilage and neural tissue regeneration, and antimicrobial peptides self-assemble into nanofibrous traps that capture and destroy pathogens. Serum albumins co-assembled with PLGA yield supraparticles with enhanced encapsulation efficiency, while a nanoadaptor platform based on an Fc gamma receptor 1-albumin fusion protein enables non-covalent antibody immobilization for multi-specific nanobodies in immunotherapy. Natural and synthetic polyelectrolytes—chitosan, dextran sulfate, hyaluronic acid, polylysine and polyethylene glycol—contribute electrostatically driven assembly, improved drug solubility and biodegradability. Natural bioactive compounds add a remarkable twist: plant-derived molecules such as curcumin, ginsenoside Rg3 and berberine can self-assemble directly into therapeutic nanostructures through pi-pi stacking, amphiphilic balance or electrostatic interactions, producing carrier-free formulations. Supramolecular solvents, formed by the self-assembly of amphiphilic molecules into dynamic, stimulus-responsive nanostructures, round out the toolkit by boosting drug solubility, stability and membrane permeation.

On the delivery side, the review classifies assembly-based platforms into six strategies governed by a structure-function-behavior coupling paradigm. Passive targeting exploits the enhanced permeability and retention effect, in which leaky tumor vasculature and impaired lymphatic drainage allow appropriately sized nanoparticles to accumulate in tumor interstitium; recent work shows lipid nanoparticles with reduced size, near-neutral surface charge and shorter PEG-lipid acyl chains deliver mRNA more efficiently. Active targeting functionalizes carriers with ligands such as folic acid or antibodies that bind receptors overexpressed on target cells, a strategy validated in oral squamous cell carcinoma models using folate-decorated carriers loaded with the inhibitor JQ1, and extended to brain delivery with ionizable lipids that cross the blood-brain barrier. Stimuli-responsive release adds spatiotemporal control, with pH, temperature, enzyme, redox and magnetic triggers enabling on-demand payload release; one dual-responsive system exploits glutathione and esterase activity inside tumor cells to break redox balance for enhanced therapy.

The remaining strategies push boundaries further. Cell-mediated delivery co-opts the innate homing ability of macrophages and dendritic cells, with examples including macrophage-hitchhiking nanomedicines for tumor transport and inflammation-activated macrophage prodrug systems that cross the blood-brain barrier to treat meningitis. Physically assisted delivery deploys ultrasound, electric and magnetic fields to enhance penetration and accumulation, illustrated by biomimetic nanomedicines paired with ultrasound to overcome physiological barriers, a battery-free nanofluidic delivery patch that adheres to organ surfaces, and magnetic nanorobots that actively navigate to tumors for chemodynamic therapy. Combined delivery integrates multiple mechanisms—exemplified by a curcumin-bifidobacteria co-delivery system for multi-target intervention in type 2 diabetes and polymeric nanoparticles simultaneously loading an oxaliplatin prodrug and mitochondria-targeting peptides—pointing toward personalized, intelligent and multifunctional platforms.

Applications now span far beyond oncology. In tissue engineering, self-assembling peptide nanofibers sustain pro-angiogenic factor release after myocardial infarction while inhibiting cardiomyocyte apoptosis and fibrosis; liposome-GelMA hydrogels spatially segregate tetrahydrocurcumin and hepatocyte growth factor for synergistic skin wound repair; and matrix-metalloproteinase-responsive hydrogels co-assembling VEGF-mimetic and cleavable peptides reconstruct neurovascular networks after ischemic brain injury. In gene editing, virus-like particles deliver CRISPR-Cas9, base editors and prime editors as ribonucleoprotein complexes, avoiding genomic integration risks, while protein nanoparticle platforms achieve cytosolic co-delivery of nucleic acids, proteins and editing tools with efficiencies reaching 25.4 percent in murine lung epithelial cells. Even environmental science benefits: assembled hollow nitrogen-rich carbon plates accelerate persulfate-based water purification, metallic-phase transition metal dichalcogenide nanosheets remove lead from contaminated water, and phage-nanoparticle hybrids eliminate antibiotic-resistant bacteria with high specificity.

The authors are candid about the obstacles standing between laboratory promise and clinical reality. Standardization is lacking: research groups use divergent protocols for measuring drug loading, encapsulation efficiency and structural stability, undermining data comparability. Clinical validation remains thin, with most evidence limited to cell studies and small-animal models showing only short-term tumor suppression rather than long-term efficacy. Safety assessment focuses heavily on acute toxicity while immunogenicity, organ accumulation and the metabolic fate of degradation products remain poorly characterized. Regulatory hurdles compound the problem, as novel carriers lack unified evaluation standards and agencies demand extensive chronic toxicology data that lengthen timelines and inflate costs. Scalability presents its own challenges, since assembly systems exquisitely sensitive to raw-material purity, pH and temperature can degrade significantly in performance during industrial scale-up, and complex manufacturing processes keep production economically unviable for many designs.

Looking forward, the review charts a roadmap built on multi-stimuli strategies such as redox dual-responsiveness for cascade drug activation within the tumor microenvironment, multimodal theranostic platforms combining targeting, imaging and co-delivery, and the integration of artificial intelligence and big data into drug design and process optimization. Standardized evaluation frameworks, continuous automated manufacturing and interdisciplinary collaboration are identified as priorities for accelerating translation. If those pieces come together, the authors conclude, assembly-based delivery systems are positioned to evolve from elegant laboratory curiosities into the intelligent, efficient backbone of precision medicine, carrying the next generation of drugs, genes and proteins precisely where the body needs them most.

Subject of Research: Assembly-based delivery systems for targeted transport of drugs, genes and proteins in biomedical engineering

Article Title: Assembly delivery of bioactive matters: Advances, challenges, and prospects

Article References: Hu, Y., Zhong, L., Wang, P., Zhan, J., Yang, W., Qiu, X., & Hou, H. (2026). Assembly delivery of bioactive matters: Advances, challenges, and prospects. Journal of Advanced Research, 87, 963-987. https://doi.org/10.1016/j.jare.2025.12.019

Image Credits: AI Generated

DOI: 10.1016/j.jare.2025.12.019

Keywords: drug delivery, self-assembly, nanoparticles, targeted therapy, stimuli-responsive materials, peptide hydrogels, lipid nanoparticles, tissue engineering, gene editing delivery, supramolecular chemistry, theranostics, biocompatibility