Targeted Lactic Acid Regulation via Engineered Exosomes for Synergistic Metabolic and Photodynamic Tumor Therapy

Tumor cells exhibit a hyper-glycolytic phenotype, resulting in massive lactic acid (LA) production that acidifies the tumor microenvironment (TME) and fosters immunosuppression. Current lactate-targeted therapies often lack synergistic dual-directional regulation. Herein, we engineer an exosomal nanoplatform, PpIX/siRNA@EXO-LOD, to simultaneously disrupt intra- and extracellular LA homeostasis, thereby enabling synergistic metabolic and photodynamic therapy (PDT). The system integrates three key components: protoporphyrin IX (PpIX) for PDT, siRNA targeting monocarboxylate transporter 4 (MCT4) for intracellular metabolic interference, and surface-displayed lactate oxidase (LOD) for extracellular catalytic starvation. Upon epithelial cell adhesion molecule (EpCAM)-mediated targeting, the nanovesicle triggers a cascade of synergistic effects. Crucially, siRNA-mediated silencing of MCT4 induces lethal intracellular acidosis, leading to significant intracellular H₂O₂ accumulation. This elevated H₂O₂ level acts as a booster for PpIX-generated reactive oxygen species (ROS) upon laser irradiation, creating an amplified oxidative stress burst that overwhelms tumor cell defenses. Concurrently, surface-anchored LOD consumes extracellular LA, alleviates lactate-induced immunosuppression. In vivo studies demonstrate that this dual-regulation strategy effectively inhibits tumor growth, downregulates metastasis-related factors (amphiregulin (AREG), ATP-binding cassette sub-family B member 1 (ABCB1)), and reprograms the TME from an immunosuppressive state to an immunologically active state. This work presents a precision nanomedicine strategy that leverages the interplay between metabolic modulation and photodynamic amplification for enhanced cancer treatment.