A Skin and Tumor Dual-Permeable Tumoricidal Gel for cGAS-STING Activation-Enhanced Chemoimmunotherapy

Local administration of drug-encapsulated gels has shown promise for cancer treatment. However, intratumoral drug diffusion is hindered by the dense extracellular matrix. Herein, a versatile skin- and tumor-dual-permeable manganese-dimethyl sulfoxide (Mn-DMSO) gel platform, with a nanofiber structure (MnSO 4 ·2H 2 O·C 2 H 6 SO as suggested by single-crystal structure), for cancer chemoimmunotherapy is introduced, which can be locally applied either through peritumoral injection for multiple tumor types or transdermal delivery for superficial tumors. This gel has a thermoresponsive sol–gel phase transition at 37 °C and intrinsic tumoricidal and cGAS-STING activation capabilities. Importantly, in addition to being a drug reservoir and taking advantage of the tissue penetration ability of DMSO, the gel is tumor-permeable and achieves a 2.5-fold enhancement in tumor penetration of drugs compared with free ones. In multiple tumor models, a peritumorally injected Mn-DMSO gel coencapsulated with a chemodrug (gemcitabine) and an immune agonist (R848) effectively triggers cGAS-STING-mediated local and systemic antitumor responses. Furthermore, we demonstrate that topical application of the R848- and gemcitabine-coloaded Mn-DMSO gel on the skin surface enables noninvasive transdermal delivery of chemo-/immunodrugs into tumors, thereby inhibiting tumor growth and metastasis in a melanoma model. Our findings highlight a gel platform that supports both injectable and topical administration for enhanced cancer therapy.