Tumor-Microenvironment-Responsive Cell-Membrane-Coated Yolk-Shell Nanocomposites Enable Combination Therapy in Solid Tumors and Leukemia.

Conventional chemotherapeutic agents are frequently limited by off-target toxicity and suboptimal therapeutic outcomes. Nanomedicines utilizing cell membrane camouflage provide a promising strategy for precise drug delivery and multimodal combination therapy. Herein, we designed a tumor-microenvironment-responsive cell-membrane-coated nanocomposite (designated as ZnO2@MO-D@Mn-CeO2@CM), which consists of a zinc peroxide (ZnO2) core encapsulated within a drug-loaded mesoporous organosilica (MO-D, where D is doxorubicin for the 4T1 breast cancer model and daunorubicin for the C1498 leukemia model) layer, with the mesopores gated by manganese-doped cerium oxide (Mn-CeO2) nanoparticles, and coated with a homologous cell membrane (CM). This nanocomposite enables the release of therapeutic components under acidic conditions and in the presence of elevated glutathione (GSH). It facilitates a combination therapy by integrating chemotherapy, enhanced chemodynamic therapy (CDT), ferroptosis induction, and immunomodulation. Our results demonstrate that this nanocomposite effectively suppresses the progression in 4T1 solid tumor and C1498 leukemia models, demonstrating its potential as a robust combinatorial strategy.