Aged microenvironment-triggered nanoreactors rejuvenate senescent LepR<sup>+</sup> cells to remodel aged bone marrow.

The senescence(definition) of leptin receptor-positive (LepR⁺) cells in bone marrow contributes to the development of the aged bone marrow microenvironment, and rescuing LepR⁺ cell senescence holds promise for alleviating age-related osteoporosis. This study reveals that senescent LepR⁺ cells establish a pro-senescent vicious cycle driven by decreased NO, reduced Mg²⁺, and continuously accumulated reactive oxygen species (ROS). To break this cycle, we constructed an aged microenvironment-triggered nanoreactor capable of releasing NO/Mg²⁺ and scavenging ROS to reverse cellular senescence. In this system, the nanoreactor (LPM) was fabricated via a thin-film hydration method, in which L-arginine was loaded into methoxy poly(ethylene glycol)-block-poly(propylene sulfide) (mPEG-b-PPS) and stabilized by Mg²⁺-mediated crosslinking. Coating LPM with senescent LepR⁺ cell membranes generated CLPM, which exhibited superior targeting to LepR⁺ cells, efficient NO/Mg²⁺ release, and potent ROS scavenging activity. CLPM treatment effectively rejuvenated senescent LepR⁺ cells, as evidenced by reduced senescence phenotypes and enhanced bone marrow regeneration. RNA sequencing further confirmed that CLPM disrupted the vicious cycle in senescent LepR⁺ cells and remodeled the aged bone marrow. Collectively, our findings suggest that the CLPM nanoreactor offers a promising approach for rejuvenation of the aging skeletal system.