Photodynamic therapy (PDT) of cancer is limited by tumor hypoxia. Platinum nanoparticles (nano-Pt) as a catalase-like nanoenzyme can enhance PDT through catalytic oxygen supply. However, the cytotoxic activity of nano-Pt is not comprehensively considered in the existing methods to exert their multifunctional antitumor effects. Here, nano-Pt are loaded into liposomes via reverse phase evaporation. The clinical photosensitizer verteporfin (VP) is loaded in the lipid bilayer to confer PDT activity. Murine macrophage cell membranes are hybridized into the liposomal membrane to confer biomimetic and targeting features. The resulting liposomal system, termed "nano-Pt/VP@MLipo," is investigated for chemophototherapy in vitro and in vivo in mouse tumor models. At the tumor site, oxygen produced by nano-Pt catalyzation improves the VP-mediated PDT, which in turn triggers the release of nano-Pt via membrane permeabilization. The ultrasmall 3-5 nm nano-Pt enables better penetration in tumors, which is also facilitated by the generated oxygen gas, for enhanced chemotherapy. Chemophototherapy with a single injection of nano-Pt/VP@MLipo and light irradiation inhibits the growth of aggressive 4T1 tumors and their lung metastasis, and prolongs animal survival without overt toxicity.

Chemoresistance conferred by leukemia propagating cells (LPCs) in a therapy‐induced niche (TI‐niche) within the bone marrow is one of the main obstacles in leukemia treatment. Effective approaches to circumvent the TI‐niche protection and to eliminate the resident LPCs remain to be exploited. Here, developed is a niche‐targeted nanosystem using leukemic cell membrane‐coated mesoporous silica nanoparticles (DAazo@CMSN) for co‐delivering daunorubicin for leukemia cell chemotherapy and a TGFβRII neutralizing antibody (aTGFβRII) to block niche signaling. DAazo@CMSN effectively targets the TI‐niche. Through an azobenzene‐based hypoxia‐responsive linker, sequential delivery of the two active molecules overcomes niche‐mediated chemoresistance, attenuates systemic burden, and prolongs survival in a mouse model of leukemia. This work demonstrates a proof‐of‐principle for biomimetic and microenvironment‐activated multiplexed nanoparticulate drug delivery strategies for overcoming therapy‐induced chemoresistance in leukemia.