Analytical and computational chemistry approaches for mechanistic insights into nanoparticles tumor access.

Cancer nanotherapeutics has become one of the most advanced areas for basic and clinical research, yet a mechanistic consensus on how systemically administered nanoparticles (NPs) access tumors remains lacking. The enhanced permeability and retention (EPR) effect has long served as the classical paradigm to explain passive tumor accumulation, but its efficacy and clinical relevance have been increasingly questioned, especially in stroma-rich tumors. Emerging evidence, supported by high-resolution imaging technologies such as transmission electron microscopy (TEM) and intravital microscopy, reveals that transcytosis-represented non-EPR pathways play a dominant role in stroma-rich solid tumors. Understanding the mechanisms of these alternative entry routes is critical for the rational design of nanocarriers and their successful clinical translation. In this review, we outline the major pathways and characteristics of nanocarrier tumor access, summarize analytical and imaging strategies for probing nano/bio interactions in nanoparticle tumor entry, and highlight computational chemistry tools for high-throughput prediction of tumor access mechanisms. We further discuss future opportunities for integrating analytical and computational approaches to rationally design nanocarriers and guide personalized nanomedicine.