Transport of Engineered Nanoparticles in Solid Tumors: Mechanistic Barriers and Emerging Delivery Strategies

Upon systemic injection, targeted delivery and site-specific tumor accumulation of nanoparticle-based medicines are major challenges. Moreover, their complex design, batch-to-batch variability, particle size heterogeneity, and surface charge variation alter the targeting and biodistribution of injected nanomedicines. We have reviewed how tumor complexity profoundly affects nanoparticles' tumor transport, penetration, and retention. In this article, the enhanced permeability and retention (EPR) mechanism and active transport and retention (ATR) principles defining nanoparticles' tumor accumulation have been discussed. Enhanced permeability and retention support nanoparticles' passive entry into the tumor through endothelial cell gaps, whereas active transport and retention allow nanoparticles' entry through active endothelial transport processes. Critical issues of tumor barriers and stimulus-responsive approaches for enhanced tumor delivery of nanoparticles have also been discussed. By integrating the major delivery bottlenecks with evolving alternative solutions, this review provides a framework to support rational nanocarrier design and their emerging tumor delivery strategies.