Molecular Engineering of the Nano‐Bio Interface for Programmable and Precision Protein Delivery

Abstract

ABSTRACT Protein therapeutics offer unparalleled specificity and immediate bioactivity for addressing complex pathologies; however, their vast therapeutic potential is fundamentally constrained by intrinsic structural vulnerability and the formidable barrier of cellular membrane impermeability. This review delineates the transformative paradigm shift in nanoparticle‐mediated protein delivery, where advanced molecular engineering enables the precise orchestration of the nano‐bio interface and exceptional spatiotemporal resolution. We systematically summarize a diverse repertoire of cutting‐edge nanoplatforms—including lipid nanoparticles, polymeric assemblies, porous nanomaterials, and supramolecular architectures—highlighting how their chemical compositions and structural motifs are tailored to navigate multi‐scale physiological barriers. A central emphasis is placed on strategic innovations in high‐efficiency protein encapsulation, organ‐selective targeting, and the critical transition from endosomal sequestration to cytosolic liberation, all of which are pivotal for maximizing therapeutic potency. Furthermore, we critically address the current challenges in tissue‐specific delivery and envision future frontiers, such as artificial intelligence (AI)‐driven nanocarrier discovery, long‐term biosafety, the path toward manufacture and clinical translation. By bridging materials chemistry with the complex cell biology of proteins, this review provides a visionary roadmap for the next generation of delivery systems, aiming to redefine the landscape of protein‐based molecular medicine.