Navigating the Endothelial Barrier: A Multiscale Framework for Precision Nanomedicine

ABSTRACT The vascular endothelium is the final and critical barrier that systemically administered nanoparticles (NPs) must navigate to reach their therapeutic targets. While the macroscale biodistribution patterns and general NP design principles have been extensively studied, there is a significant gap in understanding the mechanistic links between nanoscale interactions and mesoscale events that control NP translocation across the endothelium. This review fills this gap by integrating insights across Å‐to‐nm molecular interactions, nm‐to‐µm junctional dynamics, and µm‐to‐mm endothelial heterogeneity in physiological and pathological contexts. After dissecting the multiscale architecture of the vascular endothelium, which underpins the transcellular and paracellular transport pathways, the physicochemical properties of NPs biasing molecular recognition within the barrier were analyzed, employing molecular modeling and super‐resolution imaging to reveal “nano‐signatures” predictive of transport pathways. Furthermore, the NP‐induced mechanical reprogramming of VE‐cadherin and actomyosin network, converting paracellular leakage from a stochastic event to a programmable process, was elucidated. Finally, we discuss how NP transformations differently modulate barrier penetration by dictating interfacial interactions. By synthesizing these datasets, a cohesive mechanistic framework that offers a conceptual and practical blueprint for the rational design of nanomedicines and safety‐by‐design strategies was proposed, thereby enhancing the therapeutic efficacy and minimizing adverse effects.