Starvation-amplified CO generation for enhanced cancer therapy via an erythrocyte membrane-biomimetic gas nanofactory

Abstract

Carbon monoxide (CO)-based gas therapy has emerged as an attractive therapeutic strategy for cancer therapy. However, the main challenges are the in situ-triggered and efficient delivery of CO in tumors, which limit its further clinical application. Herein, we developed an erythrocyte membrane-biomimetic gas nanofactory (MGP@RBC) to amplify the in situ generation of CO for combined energy starvation of cancer cells and gas therapy. This nanofactory was constructed by encapsulating glucose oxidase (GOx) and Mn₂(CO)₁₀ (CO-donor) into the biocompatible polymer poly(lactic-co-glycolic acid), obtaining MGP nanoparticles, which are further covered by red blood cell (RBC) membrane. Because of the presence of proteins on RBC membranes, the nanoparticles could effectively avoid immune clearance in macrophages (Raw264.7) and significantly prolong their blood circulation time, thereby achieving higher accumulation at the tumor site. After that, the GOx in GMP@RBC could effectively catalyze the conversion of endogenous glucose to hydrogen peroxide (H₂O₂) in the presence of oxygen. The concomitant generation of H₂O₂ could efficiently trigger CO release to cause dysfunction of mitochondria and activate caspase, thereby resulting in apoptosis of the cancer cells. In addition, the depletion of intratumoral glucose could starve tumor cells by shutting down the energy supply. Altogether, the in vitro and in vivo studies of our synthesized biomimetic gas nanofactory exhibited an augmentative synergistic efficacy of CO gas therapy and energy starvation to inhibit tumor growth. It provides an attractive strategy to amplify CO generation for enhanced cancer therapy in an accurate and more efficient manner. STATEMENT OF SIGNIFICANCE: Carbon monoxide (CO) based gas therapy has emerged as an attractive therapeutic strategy for cancer therapy. In this study, we developed an erythrocyte membrane biomimetic gas nanofactory to amplify the in-situ generation of CO for combined cancer starvation and gas therapy. It is constructed by coating glucose oxidase (GOx) and CO donor-loaded nanoparticles with erythrocyte membrane. Due to the erythrocyte membrane, it can effectively prolong blood circulation time and achieve higher tumor accumulation. After accumulated in tumor, endogenous glucose can be effectively catalyzed to hydrogen peroxide, in-situ amplified CO release to induce the apoptosis of cancer cells. In addition, depleting glucose can also starve tumor cells by shutting down the energy supply. Overall, our biomimetic gas nanofactory exhibits an augmentative synergistic efficacy of CO gas therapy and starvation to increased tumor inhibition. It provide a novel strategy to deliver CO in an accurate and more efficient manner, promising for combined cancer therapy in future clinical application.

Keywords: Biomimetic gas nanofactory; CO-based gas therapy; Erythrocyte membrane; Starvation therapy; Synergistic effect.