Biomimetic LHRH-targeted nanogels for spatiotemporal-enhanced chemo-dynamic therapy of cancer.

Efficient delivery of therapeutic agents to target lesions persists as a significant challenge in cancer therapy. Herein, we report a biomimetic, near-infrared (NIR)/ultrasound (US)-responsive bifunctional drug delivery system that provides spatiotemporally programmed chemo-photodynamic therapy (PDT)/sonodynamic therapy (SDT) for prostate cancer. The designed formulation comprises reduction-sensitive nanogels encapsulated within RBC membranes, surface-functionalized with LHRH for targeted delivery (termed LHRH-RBC/Ce6-NG/HCPT). Chlorin e6 (Ce6), a photosensitizer and sonosensitizer, was embedded within the RBC membrane shell, while the anticancer compound 10-hydroxycamptothecin (HCPT) was encapsulated within the nanogel core structure of poly(L-glutamic acid)-poly(L-phenylalanine-co-L-cystine) nanogels. Compared with free Ce6 and HCPT, the designed formulation markedly extended systemic retention and improved intratumoral deposition. Furthermore, tumor‑localized NIR or US stimulation induced the production of reactive oxygen species (ROS), which enhanced nanovesicle uptake by increasing tumor cell membrane fluidity and concurrently disrupted the RBC membrane, leading to the rapid, intracellular glutathione-triggered release of HCPT. The released HCPT further synergized with PDT/SDT to amplify ROS generation and exacerbate mitochondrial dysfunction, thereby enhancing tumor cell killing. The spatiotemporally coupled dynamic-chemotherapy maximized on-tumor efficacy while minimizing off-target toxicity. In vivo studies confirmed that, LHRH-RBC/Ce6-NG/HCPT achieved potent synergistic effects in both PDT/chemotherapy and SDT/chemotherapy, demonstrating its potential as an effective and safe treatment strategy for prostate cancer.