Ultrasound-activated biomimetic nanoplatform enables long-acting chemo-sonodynamic therapy of prostate cancer and lymphatic metastasis.

The effective treatment of prostate cancer with lymphatic metastasis remains limited by insufficient drug retention and the lack of controllable exposure in both primary tumors and metastatic lymph nodes. Here, we report a biomimetic, reduction- and ultrasound-responsive hollow mesoporous silica nanoplatform (HMSN@TCM/Ce6) that enables long-acting, spatiotemporally regulated chemo-sonodynamic therapy across tumor and lymphatic sites. The system comprises a reduction-sensitive hollow silica core encapsulating 10-hydroxycamptothecin (HCPT) and a tumor cell membrane (TCM) shell embedding chlorin e6 (Ce6). This hierarchical design integrates sustained intratumoral retention, homologous targeting, and externally triggered sonodynamic activation within a single platform. The biomimetic TCM coating prolongs systemic circulation and facilitates preferential tumor accumulation, while the hollow silica core functions as a long-term reservoir for redox-responsive HCPT release. Upon ultrasound irradiation, localized ROS generation induces transient membrane perturbation, which accelerates nanoparticle internalization and on-demand payload release. Importantly, ultrasound-enhanced tumor retention further promotes nanoparticle redistribution toward tumor-draining lymph nodes, establishing a multistage tumor-to-lymph node therapeutic relay that enables secondary drug accumulation and cytotoxicity. Comprehensive in vitro and in vivo evaluations demonstrate prolonged pharmacokinetics, elevated tumor and lymph node accumulation, and effective inhibition of both primary tumors and metastatic lymph nodes, while maintaining favorable biosafety. Beyond conventional sustained-release depots, this work introduces an externally controllable long-acting delivery paradigm in which a single systemic dose forms sequential, site-specific therapeutic depots. This strategy provides a versatile framework for intelligent long-acting nanomedicines with potential for precision and minimally invasive cancer therapy.