Rohan M. Shah, Indu Pal Kaur, Snehal R. Jadhav
The surface of a nanocarrier is the frontline interface between its therapeutic cargo and the complex biological milieu it encounters. While traditional drug delivery research has focused on payload optimisation, emerging challenges, such as antimicrobial resistance, chronic inflammation, and site-specific pathology, demand a strategic pivot toward a surface-first paradigm. This review proposes a surface-first framework for nanocarrier engineering - prioritising dynamic, responsive, and selective surface interactions over conventional passive shielding. It critically evaluates the limitations of conventional surface modifications (e.g. , PEGylation) and spotlights zwitterionic coatings and platelet-cloaked nanoparticles as flagship examples of next-generation stealth and targeting. Using infection-responsive systems as exemplars, we show how surface chemistry not only improves pharmacokinetics and biodistribution but also serves as a precision trigger (e.g., pH-activated charge reversal and MMP-cleavable linkers) for on-demand activation at the site of need. We highlight the need for standardised surface-characterisation protocols, modular manufacturing schemes, and integrated diagnostic–therapeutic interfaces to support clinical translation. Embracing a surface-first approach is both timely and essential to drive the future of targeted therapy. While interfacial principles are well established, we focus on an infection-centred, mechanism-first synthesis that links core–surface co-design to controlled release. • Infection-focused surface-first framework mapping barriers to interface logic. • Mechanistic Penetrate → Activate → Adhere and kill schema spanning key surface chemistries. • Surface cues drive sensing; core mechanics set release-integrated co-design model. • Quantifies interface trade-offs, switching kinetics and failure modes in infection. • Advocates infected-media interfacial assays and modular, scalable fabrication.