The unique characteristics of the tumor microenvironment (TME) could be exploited to develop antitumor nanomedicine strategies. However, in many cases, the actual
therapeutic effect is far from reaching our expectations due to the notable
tumor heterogeneity. Given the amplified characteristics of TME regulated by vascular disrupting agents (VDAs), nanomedicines may achieve unexpected improved efficacy. Herein, we fabricate platelet membrane-fusogenic
liposomes (PML/DP&PPa), namely "platesomes", which actively load the
hypoxia-activated pro-
prodrug DMG-PR104A (DP) and physically encapsulate the
photosensitizer pyropheophorbide a (PPa). Considering the different stages of
tumor vascular collapse and shutdown induced by a VDA combretastatin-A4
phosphate (CA4P), PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P. First, CA4P-mediated
tumor hemorrhage amplifies the enhanced permeation and retention (EPR) effect, and the platesome-biological targeting further promotes the
tumor accumulation of PML/DP&PPa. Besides, CA4P-induced vascular occlusion inhibits
oxygen supply, followed by
photodynamic therapy-caused acute tumor hypoxia. This prolonged extreme
hypoxia contributes to the complete activation of DP and then high inhibitory effect on
tumor growth and
metastasis. Thus, such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves
tumor drug delivery and boosts tumor hypoxia-selective activation, and provides a preferable
solution to high-efficiency
cancer therapy.