Realizing active targeting in cancer nanomedicine with ultrasmall nanoparticles

Ultrasmall nanoparticles (usNPs) have emerged as promising theranostic tools in cancer nanomedicine. With sizes comparable to globular proteins, usNPs exhibit unique physicochemical properties and physiological behavior distinct from larger particles, including lack of protein corona formation, efficient renal clearance, and reduced recognition and sequestration by the reticuloendothelial system. In cancer treatment, usNPs demonstrate favorable tumor penetration and intratumoral diffusion. Active targeting strategies, incorporating ligands for specific tumor receptor binding, serve to further enhance usNP tumor selectivity and therapeutic performance. Numerous preclinical studies have already demonstrated the potential of actively targeted usNPs, revealing increased tumor accumulation and retention compared to non-targeted counterparts. In this review, we explore actively targeted inorganic usNPs, highlighting their biological properties and behavior, along with applications in both preclinical and clinical settings.