Self-Assembling Carriers Could Redefine How Drugs Reach Their Targets

Drug delivery has long been one of medicine’s most stubborn engineering problems: getting the right therapeutic molecule to the right cell, at the right time, without degrading it along the way or harming healthy tissue in the process. A comprehensive new review published in the Journal of Advanced Research argues that a rapidly maturing technology known as assembly-based delivery systems, or ADS, may finally provide the tools needed to solve it. Written by Yi Hu, Linfang Zhong, Pengqi Wang, Jiamian Zhan, Wenhui Yang, Xiaozhong Qiu and Honghao Hou, the review synthesizes years of progress in molecular self-assembly and smart functional materials, mapping out how these platforms can carry drugs, genes and proteins with a degree of structural designability, functional tunability and precise responsiveness that conventional carriers struggle to match.

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