SR-717

The activation of cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) has been recognized as one of the most promising immunotherapeutic strategies to induce innate antitumor immune responses. However, it is far from effective to just activate the cGAS-STING pathway, owing to abundant immunosuppressive cells that infiltrate the tumor microenvironment (TME) to impair antitumor immunity. Here, we present the smart design of biodegradable Mn-doped mesoporous silica (MM) nanoparticles with metal-organic framework (MOF) gating and hyaluronic acid (HA)-modified erythrocyte membrane (eM) camouflaging to coload cisplatin (CDDP) and SR-717 (a STING agonist) for long-circulating tumor-tropism synergistic chemo-metalloimmunotherapy by cascade cGAS-STING activation. Once internalized by tumor cells, the acidity/redox-responsive gated MOF rapidly disintegrates to release SR-717 and exposes the dual-responsive MM to decompose with CDDP release, thus inducing damage to double-stranded DNA (dsDNA) in cancer cells. As tumor-specific antigens, these dsDNA fragments released from tumor cells can trigger cGAS-STING activation and enhance dendritic cell (DC) maturation and cytotoxic T cell (CTL) infiltration, thus giving rise to excellent therapeutic effects for efficient tumor regression. Overall, this custom-designed biodegradable long-circulating nanoagonist represents a paradigm of nanotechnology in realizing the synergistic cooperation of chemotherapy and metalloimmunotherapy based on cascade cGAS-STING activation for future oncological applications.

Neuroinflammation is intimately associated with poor prognosis in patients with subarachnoid hemorrhage (SAH). Alpha-lipoic acid (ALA), a disulfide antioxidant, has been shown to be neuroprotective in an in vivo model of neurological injury; however, the role of ALA in SAH has never been evaluated. In this study, the Sprague–Dawley rats SAH model was induced by endovascular perforation method. ALA was transplanted intravenously into rats, and SR-717, a stimulator of interferon genes (STING) agonist, was injected intraperitoneally. The effects of ALA on early brain injury were assayed by neurological score, hematoxylin and eosin staining and Nissl staining. Immunohistochemistry staining and Western blotting were used to analyze various proteins. ALA significantly reduced STING- NLRP3 protein expression and decreased cell death, which in turn mitigated the neurobehavioral dysfunction following SAH. Furthermore, coadministration of ALA and SR-717 promoted STING-NLRP3 signaling pathway activation following SAH, which reversed the inhibitory effect of ALA on STING-NLRP3 protein activation and increased the neurological deficits. In conclusion, ALA may be a promising therapeutic strategy for alleviating early brain injury after SAH.