Engineering the Biological Identity of Poly(lactic-co-glycolic Acid) Nanocarriers: Protein-Corona Dynamics, Functional Reprogramming, and Translational Fate

Poly(lactic-co-glycolic acid) (PLGA) nanocarriers can be engineered by varying polymer architecture, particle dimensions, surface chemistry, ligands, coatings, and cargo; however, biological exposure subsequently remodels the interface encountered by cells and tissues. This narrative review examines how this acquired biological identity may help explain translational failure between favorable formulation-level or in vitro properties and downstream in vivo performance. Across experimental and preclinical studies, serum or tissue-fluid composition, competitive protein exchange, physiological flow, complement and immunoglobulin recognition, ligand masking, tissue sequestration, and altered protein accessibility can redirect uptake, clearance, barrier interaction, biodistribution, efficacy, and safety. Corona formation, however, is not uniformly detrimental: selected interfaces can support dendritic-cell activation, blood-cell hitchhiking, or endogenous apolipoprotein-mediated targeting. We organize the literature as a biological stress-test continuum extending from the engineered pre-corona state through the acquired interface, cellular function, tissue transport, and whole-organism fate, while explicitly distinguishing direct PLGA evidence, mechanistically supported PLGA findings, associative PLGA observations, and comparator-only evidence. No clinical data or meta-analysis are included. The central translational implication is that PLGA performance should be judged by the robustness of its intended function after biologically relevant reprogramming rather than by pristine-particle properties alone.