Biomimetic Chitosan Nanogels Codeliver Drug/Small Activating RNA for Metastasis-Inhibited Necroptosis Therapy of Ovarian Cancer

Ovarian cancer remains the leading cause of gynecologic malignancy-related deaths. Developing novel nanoplatforms to overcome the low efficacy of chemotherapy and advanced metastasis in ovarian cancer is crucial. Here, we report biomimetic chitosan nanogels (CH NGs) designed to codeliver gambogic acid (GA) and MAS1 small activating RNA (saMAS1). The formed CH NGs/GA/saMAS1 camouflaged with ovarian cancer cell membranes (CM) can release GA in a pH-responsive manner, target cancer cells, and induce the killing effects through GA-mediated necroptosis. Meanwhile, saMAS1 upregulates MAS1 expression, counteracting the activation of angiotensin II receptor type 1 (AGTR1) and thereby inhibiting the renin-angiotensin system (RAS) signaling pathway, subsequently impeding metastasis. The therapeutic efficacy of CH NGs/GA/saMAS1@CM NGs regarding primary tumor killing and metastasis inhibition was further confirmed using ovarian mouse models. These biocompatible CH NGs represent a promising advanced nanomedicine formulation to tackle ovarian cancer through metastasis-inhibited necroptosis following the codelivery of GA and saMAS1.