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Nanomedicines (NMs) have emerged as a promising approach for revolutionizing cancer treatment outcomes, mainly due to their benefits in the tumor-targeted delivery of therapeutics. The preferential accumulation of NMs in tumors has been widely verified by macroscopical technologies. Accordingly, several classic and emerging targeting mechanisms have been proposed to support the tumor-specific delivery of NMs. The targeting mechanism has been a topic of intense interest and controversy in the field of NMs development. Especially, the mechanisms by which NMs target tumor remain elusive. This topical review mainly discussed the evolution of the targeting mechanisms, crucial issues associated with each mechanism, and confused debates among the mechanisms. The targeting mechanisms of tumor-specific NMs discussed here include the enhanced permeability and retention (EPR) effect, protein corona-mediated targeting delivery, circulating cell mediated transportation, and transcytosis. It is of great significance for ultimate clinical translation to have more comprehensive considerations on the mechanism driving the pathway of NMs toward tumors. Our thoughts in this review are expected to provide a comprehensive understanding of the mechanisms and elicit thorough explorations of new mechanisms to renovate the knowledge framework of NMs delivery.

Navigations of the targeting pathway of nanomedicines toward tumor