Enhanced permeability and retention (EPR) effect: Advances in nanomedicine for improved tumor targeting

The enhanced permeability and retention (EPR) effect driven by abnormal tumor vasculature and impaired lymphatic drainage has long been considered a cornerstone of nanomedicine-based cancer therapy. While preclinical studies demonstrate substantial nanoparticle accumulation in solid tumors via passive targeting, clinical outcomes remain inconsistent due to the heterogeneous and dynamic nature of the EPR effect across tumor types and patients. Tumor vascular density, elevated interstitial fluid pressure, and stromal barriers frequently restrict drug penetration and retention, limiting therapeutic efficacy. This review provides a critical and translational perspective on strategies to amplify the EPR effect, including vascular normalization, transient modulation of blood flow, hypertension induction, and integration with active targeting ligands. We also highlight tumor microenvironment remodeling, image-guided delivery, and patient-specific predictive diagnostics as emerging avenues to enhance clinical predictability. By bridging mechanistic insights with therapeutic innovation, we propose a roadmap to reengineer EPR-based delivery systems for more consistent, potent, and personalized nanomedicine in solid tumor management.