Cell Membrane Biophysics as a Therapeutic Interface for Nanomedicine: From Disease-Associated Remodeling to Translational Qualification

Abstract

Highlights What are the main findings? Disease-associated changes in lipid organization and fluidity, membrane mechanics, receptor organization, glycocalyx architecture, and bioelectric states create context-dependent therapeutic opportunities and delivery barriers. An interface-centered framework connects disease-remodeled membrane states to mechanistically matched nanomedicine strategies and a function-centered pathway for translational qualification. What are the implications of the main findings? Candidate membrane cues should be prioritized when they are accessible, disease-enriched, and functionally linked to recognition, transport, or therapeutic response. Clinical translation requires measurable membrane-dependent function supported by interaction evidence, membrane-specific quality and potency, context-matched validation, in vivo pharmacology and safety, and reproducible manufacturing. Abstract Nanomedicine has yielded clinically useful platforms, including liposomes, albumin-bound nanoparticles, and lipid nanoparticles; yet, many systems translate poorly because of nonspecific biodistribution, limited target-site accumulation, inefficient cellular uptake and intracellular delivery, immune clearance, and off-target toxicity. These bottlenecks are often shaped at cell membrane interfaces, where therapeutic materials are recognized, retained, internalized, or cleared and may elicit unsafe responses. Here, we frame cell membrane biophysics as a therapeutic interface for nanomedicine. We examine how lipid organization and fluidity, mechanics, electrochemical state, glycocalyx architecture, and membrane protein identity shape recognition, adhesion, endocytosis, fusion, trafficking, immune responses, and drug release. We assess how disease-associated membrane remodeling can create candidate therapeutic entry points and delivery barriers across cancer, neurodegeneration, inflammation, infection, and vascular disease. We then analyze receptor-mediated targeting, lipid-domain-associated uptake, membrane-coated nanocarriers, engineered extracellular vesicles, and hybrid platforms, with explicit context-of-use definitions and design boundaries. Finally, we propose translational qualification through function-linked critical quality attributes, mechanism-relevant potency assays, context-matched models, in vivo pharmacology and immune safety, scalable manufacturing, and regulatory evaluation. Progress will depend less on descriptive membrane mimicry than on measurable, reproducible, and qualified membrane-dependent functions.