Transport phenomena in polymeric nanoparticle drug delivery systems: linking soft-matter design to biological performance

Abstract

Polymeric nanoparticles, particularly nanogels and other soft polymeric carriers, have emerged as promising platforms for precision nanomedicine because their physicochemical and mechanical properties can be engineered to regulate the transport of biological entities and the release of therapeutic agents. Despite significant advances in stimulus-responsive materials and surface engineering, clinical translation remains limited because the influence of soft-matter properties on transport across complex in vivo biological barriers is not yet fully understood. Current design strategies often emphasize particle size, surface charge, and loading efficiency, but they do not adequately account for the combined effects of polymer mechanics, hydration, deformation, and interfacial interactions on biological performance. This review examines polymeric nanoparticle drug delivery from a transport-oriented soft-matter perspective. Key soft-matter parameters, including elastic modulus, swelling ratio, crosslink density, mesh size, viscoelastic relaxation, and interfacial hydration, are considered alongside major transport mechanisms such as diffusion, convection, deformation-assisted transport, interfacial interactions, and transport-reaction coupling. Their roles in blood circulation, protein corona formation, endothelial translocation, extracellular matrix penetration, mucosal transport, cellular uptake, intracellular trafficking, and drug release are critically assessed. Emerging methodologies, including microfluidic tissue-mimetic systems, multiscale modelling, and artificial intelligence-assisted nanomedicine design, are also discussed as tools for predictive, transport-informed system engineering. To integrate these concepts, we propose the Transport–Soft Matter Coupling Framework (TSMCF), which defines soft polymeric nanoparticles as adaptive mechanical systems in which transport mechanisms evolve across sequential biological barriers. Rather than viewing nanocarriers in isolation, this framework considers changes in softness, hydration, deformability, and release behaviour during biological transport. The TSMCF offers a mechanistic basis for the design of clinically translatable soft nanomedicines by linking polymer-network mechanics, transport phenomena, and translational performance.