Abstract
ABSTRACT
Deep and spatially uniform drug delivery remains a major challenge in nanomedicine for solid tumor therapy. During delivery, nanoparticles must sequentially traverse multiple biological barriers, from systemic circulation and tumor accumulation to vascular extravasation, basement‐membrane crossing, interstitial penetration, and cellular internalization. In this review, we distinguish the sheet‐like perivascular basement membrane from the fibrillar, hydrated interstitial extracellular matrix and discuss how intertumoral, intratumoral, and stage‐specific heterogeneity alters the dominant transport barriers across different tumor contexts. We then summarize three complementary strategies for engineering nanoparticles to improve deep tumor penetration: 1) Nanocarrier design, which tunes particle shape, size, surface charge, mechanical stiffness, and ligand presentation to balance cellular interactions and interstitial mobility; 2) Vascular and Stromal Modulation, which alleviates transport barriers through vascular normalization, transient basement‐membrane modulation, controlled extracellular‐matrix remodeling, and regulation of matrix production by cancer‐associated fibroblasts; 3) Active and Assisted Transport, which promotes trans‐barrier delivery through transcytosis, self‐propelled nanomotors, and externally applied physical energy. We discuss the associated challenges and optimization strategies, particularly those related to spatial penetration, tumor accumulation, model‐dependent efficacy, and safety. Finally, we highlight the translational limitations and future opportunities of tumor‐penetrating nanomedicines from a clinical perspective.