Abstract The Enhanced Permeability and Retention (EPR) effect is a foundational concept used to rationalize nanomedicine development for cancer treatment and diagnostics. The attainable efficacy of passive tumor targeting due to EPR remains ambiguous owing to pervasive opsonization of nanoparticles. To address this, we developed nanomaterials with complete resistance to opsonization, exceptionally long systemic circulation, and used them to study the limits of the EPR in triple-negative breast cancer. Tumors exerted no impact on pharmacokinetic profiles, which were indistinguishable between healthy and tumor-bearing mice. Tumors were the primary accumulation sites and our data revealed that the maximum average achievable tumor accumulation via EPR is proximate to 60 %ID/g, tumor- to-liver selectivity is 4-to-1, and the optimal D H to fully exploit EPR lies between 18 and 54 nm. The significant heterogeneity observed in tumor accumulation, however, indicates that nanomedicines cannot achieve consistent efficacy across different patients by relying solely on EPR.

Exploring the Limits of EPR-driven Tumor Accumulation with Non-opsonizing Nanomaterials