O 2 -Generation-Enhanced Responsive Starvation/Photothermal Synergistic Tumor Therapy Based on the AuNRs@MnO 2 @SiO 2 Nanocarrier and Thermosensitive Biomimetic Camouflaging.

Cancer starvation/photothermal combined tumor therapy (CST/PTT) has attracted great interest attributed to their mutual compensation and synergistically enhanced effect. However, the very low O 2 supply in the tumor microenvironment (TME) greatly limits the CST efficiency of glucose oxidase (GOx). Additionally, the easy degradation in blood circulation and significant off-target effects are big challenges for clinical applications of the GOx-based CST. In this study, a drug delivery system (DDS) with specific tumor-targeted GOx delivery, near-infrared (NIR) light and TME responsive O 2 generation, NIR-responsive glucose consumption, high GOx loading, and efficient NIR photothermia was developed. Positively charged AuNRs@MnO 2 @SiO 2 nanoparticles (named AMS + NPs) were synthesized. GOx was covalently loaded with a high loading ratio of 36.0%. Finally, a thermosensitive biomimetic hybrid membrane composed of a thermosensitive lipid (TSL) membrane, red blood cell membrane (RBCM), and 4T1 cancer cell membrane (CCM) was coated on the NPs through a double-layer strategy. The AMS + -G@TSL@[RBC-CC-TSL]M NPs consumed 32.7 times glucose at 50 °C as that at 37 °C and generated 4.9 times O 2 upon NIR laser irradiation. The thermosensitive biomimetic NPs showed an efficient targeting capability to the homotypic 4T1 cancer cells/tumors accompanied by good biocompatibility, macrophage evading capability, high cancer cell cytotoxicity, and excellent antitumor efficacy. The tumor growth inhibition ratio with NIR laser irradiation reached 92.8%. The AMS + -GOx@TSL@[RBC-CC-TSL]M NPs provide a smart, efficient, safe, PTT/CST combined DDS for highly efficient tumor therapy.