<p>Cancer stem cells (CSCs), characterized by their limitless self-renewal and differentiation capabilities, pose a significant challenge to the efficacy of radiotherapy (RT). CSCs exhibit radiation resistance through enhanced DNA damage repair mechanisms and modulation of the tumor microenvironment. Targeted therapy against CSCs remains a formidable challenge. To address this issue, we have developed a biomimetic nano-platelet (PMA) designed to actively target CSCs deep within tumors. The core of PMA comprises MnO₂ nanoparticles loaded with aspirin, while its outer layer is coated with a platelet membrane enriched in P-selectin and CD44 proteins. Guided by the platelet membrane, PMA precisely targets CSCs, whereupon the MnO₂ responds to the acidic tumor microenvironment, releasing aspirin. Then, aspirin subsequently downregulates pluripotency proteins such as NANOG and OCT4, thereby specifically targeting and eliminating CSCs. Additionally, MnO₂ catalyzes hydrogen peroxide to generate oxygen, alleviating hypoxic conditions and enhancing the effectiveness of RT, leading to further eradication of tumor cells. Both in vitro cell experiments and in vivo tumor models demonstrate that the engineered PMA synergizes with radiotherapy to eliminate CSCs and inhibit tumor growth. This innovative approach not only underscores precise targeting but also ensures excellent biocompatibility, offering new insights into sensitizing radiotherapy.</p>