A polymer-free, tumor-microenvironment responsive sol–gel platform for spatiotemporal STING activation and self-amplifying immunotherapy

Abstract

Non-nucleotide stimulators of interferon gene (STING) agonists hold promise as immunotherapeutic agents for cancer immunotherapy and postsurgical adjuvant therapy. However, as a prototypical STING agonist, DMXAA suffers from rapid degradation, off-target toxicity, and poor tumor accumulation. Here, we present a polymer-free iRGD-buSS-camptothecin-based sol capable of enhancing drug penetration, activating immune responses, and enabling therapeutic monitoring. This multifunctional sol integrates a tumor-homing cyclic peptide with reducible disulfide-linked camptothecin crosslinkers, enabling in situ sol–gel transition to achieve spatiotemporally controlled delivery of the STING agonist DMXAA into tumor parenchyma. The resulting hydrogel forms a durable drug reservoir with a >30 day tumor retention, where a single low-dose DMXAA (0.2 mg kg⁻¹) triggers potent tumor regression, extends survival, and establishes long-term immunological memory—effectively activating systemic immune surveillance to suppress metastasis. Our strategy synergizes molecularly engineered tumor-targeting precision with spatiotemporal control of STING-driven innate immune activation, circumventing the pharmacological limitations (poor delivery and systemic toxicity) of conventional small-molecule agonists.