Transcytosis, traditionally regarded as biological, constitutes an intrinsic and powerful pathway for macromolecule transport across endothelial and epithelial barriers. The emerging concept of Enhanced Transcytosis and Retention (ETR) is distinct from passive extravasation or tissue leakiness. It recasts nanocarrier delivery as an orchestrated chain of interfacial equilibria in which encoded surface chemistry directs receptor recognition, active barrier crossing, and subsequent accumulation within target tissues. Here, we delineate the chemical framework underpinning ETR-mediated delivery, emphasizing that the chemical identity of a nanocarrier, i.e., its surface functional groups, coordination motifs, hydration shell, reactive ligands, surface free energy, and biocorona, dictates a hierarchical sequence of interactions. To enable ETR access, we propose a triadic interaction model among the nanocarrier, an endogenous or engineered protein-based material, and a specific cellular receptor. This architecture represents a fundamental shift from conventional two-entity protein-adsorption frameworks, converting inherently stochastic protein deposition into a chemically programmable, design-driven active transport process. At the inner interface (between nanocarrier and protein material), surface functional groups, roughness, and topology determine the composition, orientation, and reactivity of a given biomolecule, such as endogenous or engineered proteins. At the outer interface (protein-cell receptor), these nanocarrier–protein complexes engage cell receptors through amino acid sequence-specific molecular recognition, topological complementarity, hydrogen-bond cooperativity, and electrostatic complementarity that collectively trigger ETR active access. Such an ETR framework, first exemplified in solid tumors (e.g., pancreatic cancer and triple negative breast cancer), now extends to diverse pathological contexts including the blood-brain barrier and dystrophic muscle. By viewing ETR drug delivery through a chemical lens, this manuscript integrates structure–reactivity principles with biological transport, providing a molecularly actionable framework for otherwise inaccessible tissues. Noteworthy, artificial intelligence (AI) guided protein engineering, using strategies such as point mutagenesis and noncanonical amino-acid substitution, will enable the creation of highly optimized and artificial ligands that assemble ETR-activating units with molecular-level precision.

Acc. Chem. Res. 2026, 59, 7, 1284–1296 https://doi.org/10.1021/acs.accounts.6c00062