Engineered nanomedicines with enhanced tumor penetration

[Display omitted] •Modulation of tumor microenvironments for enhancing tumor penetration of nanomedicines.•Nanoparticle optimization for upregulating tumor penetration of nanomedicines.•Tumor-penetrating peptides mediating transcellular transport to promote tumor penetration of nanomedicines.•Multifunctional transformable nanoparticles with upregulated tumor penetration.•Strategy prediction for improving tumor penetration of nanomedicines. Nanomedicine has been extensively explored to enhance the efficacy of chemotherapy with modest therapeutic efficacy in the clinic, owing to various factors. A primary factor is inefficient tumor penetration caused by specific tumor microenvironments, such as insufficient blood supply, high-density tumor cells and extracellular matrix, and increased interstitial fluid pressure. To date, several strategies, including the modulation of tumor microenvironments and optimization of nanoparticle properties, have been reported to improve the tumor penetration of nanomedicines, but these traditional strategies still have limitations. Recently, with unique strategies like tumor-penetrating peptide-mediated transcellular transport, the multifunctional transformable nanoparticles have emerged as an advanced generation of nanomedicine with superior tumor penetration capabilities. In this review, the latest development and limitations of nanomedicines are summarized, and prospects for improving tumor penetration are discussed.