Lactate oxidase-engineered manganese layered double hydroxide nanoplatform amplifies cGAS-STING activation for tumor...

The cGAS-STING pathway plays a central role in antitumor innate immunity, but the therapeutic efficacy of STING agonists is often limited by insufficient tumor delivery and inadequate amplification of endogenous danger signals. Here, we developed a lactate oxidase-engineered manganese layered double hydroxide nanoplatform loaded with the STING agonist MSA-2, termed Mn-LDH-M@LOX, to establish a tumor metabolism-driven STING amplification strategy. Under mildly acidic tumor-associated conditions, Mn-LDH-M@LOX underwent structural disassembly and synchronously released manganese ions and MSA-2. Meanwhile, surface-immobilized LOX converted tumor-derived lactate into hydrogen peroxide, thereby providing an endogenous fuel for manganese-mediated ROS amplification. This cascade induced oxidative DNA damage, mitochondrial dysfunction and cytosolic mtDNA accumulation, which further reinforced cGAS-STING-related immune activation together with MSA-2 and manganese ions. In 4T1 tumor cells, Mn-LDH-M@LOX efficiently enhanced ROS generation, mitochondrial depolarization, γ-H2AX-associated DNA damage, ICD-related signals and downstream immune responses, including increased p-IRF3, IFN-β and CXCL10. In vivo, Mn-LDH-M@LOX significantly suppressed tumor growth, reduced intratumoral lactate content and decreased Ki67 expression, while promoting CRT exposure, dendritic cell maturation, CD4⁺/CD8⁺ T-cell infiltration and intratumoral cytokine/chemokine production. Moreover, no obvious systemic toxicity was observed based on body weight, blood biochemical indices, routine blood parameters and major organ histology. Overall, this work presents a lactate-fueled manganese nanocatalytic platform that converts tumor metabolic reprogramming into ROS-amplified STING activation, offering a promising strategy for enhanced tumor immunotherapy.