Stimuli-responsive delivery systems hold promise in cancer treatments. However, their application potential has been limited due to undesirable drug leaking during blood circulation and inefficient therapeutic efficacy in tumors, resulting in undesirable therapeutic outcomes. Herein, we have developed a novel redox-sensitive pegylated phospholipid, termed as DOPE-SS-PEG, which can form a glutathione (GSH)-triggered precision explosive system (GPS) for simultaneously improving circulation stability, tumor specificity, and chemosensitivity, leading to explosive anticancer effects. GPS is constructed of liposomal doxorubicin (DOX) functionalized with DOPE-SS-PEG and MnO₂ nanoparticles, which can protect liposome structure in the presence of serum GSH (20 μM), whereas converts to cationic liposome in response to intracellular GSH (10 mM), thereby enhancing circulation stability, tumor specificity, endosomal escape, and cytoplasmic delivery. Importantly, GPS can not only generate oxygen to relieve hypoxia and consequently enhance chemosensitivity, but quench GSH antioxidability to elevate the accruement of intracellular reactive oxygen species (ROS), leading to an explosion of oxidative stress induced cell injury. Particularly, in vivo studies show that GPS selectively accumulates in tumor tissues, effectively inhibits tumor growth, exhibits minimal systemic adverse effects, and consequently prolongs the survival time of tumor-bearing mice. Therefore, GPS is a unique stimuli-responsive treatment with programmed and on-demand drug delivery, as well as explosive therapeutic efficacy, and provides an intelligent anticancer treatment.

Cisplatin is a widely applied therapeutics for the treatment of osteosarcoma. However, its clinical applications have been hindered due to low efficacy and bioavailability, and particularly frequent emergence of reactive oxygen species (ROS)-decrease induced drug resistance. The transcription factor NF-E2-related factor 2 (Nrf2) is increased in cancer patients and induces poor outcome in osteosarcoma treatment, making it a novel target to improve the efficacy of chemotherapy. Herein, a hyaluronidase-responsive multi-layer liposome (HLCN) for co-delivery of cisplatin and Nrf2 siRNA (siNrf2) is developed. It is composed of Vpr_52-96 modified liposome covered with hyaluronic acid (HA). HLCN selectively accumulates in osteosarcoma by targeting tumor-specific CD44, and can be degraded by endosomal hyaluronidase to generate cationic liposome, which promotes the endosomal escape of Vpr_52-96, cisplatin and siNrf2. HLCN can effectively decrease Nrf2 level, promote ROS generation, activate itochondrial apoptotic pathway, and consequently enhance anticancer efficacy of cisplatin. Particularly, HLCN shows high cytotoxicity to osteosarcoma cells with an IC₅₀ value of about 1 μM, which is four-fold lower than liposomal cisplatin (IC₅₀ 4 μM), indicating that Nrf2 silence can significantly improve cisplatin sensitivity in cancer cells. Importantly, HLCN can remarkably inhibit tumor growth in the xenograft osteosarcoma mice with minimal systemic adverse effects. Therefore, this novel stimuli-responsive combination therapy of cisplatin and siNrf2 provides a promising strategy for the treatment of osteosarcoma.