Nanoparticle-Based Drug Delivery Systems for Anticancer Therapy: Microenvironment-Driven Strategies, Advances, and Challenges

Cancer remains a major global health challenge, and nanoparticle-based drug delivery systems have emerged as a promising strategy for targeted cancer therapy. However, clinical translation is still limited by an incomplete understanding of how nanoparticles navigate the tumor microenvironment (TME) throughout the delivery process. This review presents an integrated, stage-by-stage framework for nanoparticle design that addresses the TME barriers encountered during systemic circulation, tumor-targeted enrichment, and drug release. During systemic circulation, PEGylation, hydrophilic polymer modification, cell membrane- or exosome-based biomimetic technologies, and biomolecular corona formation are employed to prolong circulation half-life. In the tumor-targeting stage, charge-reversal surfaces, ligand conjugation, ligand shielding, and tuning of physical properties enhance tumor accumulation and cellular internalization. For drug release, molecular and structural design enables intracellular responsive release, stepwise extracellular-to-intracellular release, and sequential release to distinct target cells. Beyond summarizing these strategies, we highlight the newly proposed active transport and retention (ATR) principle as a unifying mechanistic framework that explains how nanoparticles achieve tumor accumulation through active endothelial transport and retention via tumor component interactions. We further discuss translational barriers including complex fabrication, scalability hurdles, and biocompatibility constraints, and outline emerging solutions such as novel nanoparticle fabrication methods (microfluidics, turbulent jet, and microfluidic mixing), engineered biomimetic exosomes, organ-on-a-chip evaluation platforms, and AI-driven design screening. By connecting stage-specific design strategies to the ATR framework, this review offers a mechanistic foundation for the rational design of next-generation nanomedicines.