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Current lactate\u2010targeted therapies often lack synergistic dual\u2010directional regulation. Herein, we engineer an exosomal nanoplatform, PpIX\/siRNA@EXO\u2010LOD, to simultaneously disrupt intra\u2010 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\u2010displayed lactate oxidase (LOD) for extracellular catalytic starvation. Upon epithelial cell adhesion molecule (EpCAM)\u2010mediated targeting, the nanovesicle triggers a cascade of synergistic effects. Crucially, siRNA\u2010mediated silencing of MCT4 induces lethal intracellular acidosis, leading to significant intracellular H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    accumulation. This elevated H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    level acts as a booster for PpIX\u2010generated reactive oxygen species (ROS) upon laser irradiation, creating an amplified oxidative stress burst that overwhelms tumor cell defenses. Concurrently, surface\u2010anchored LOD consumes extracellular LA, alleviates lactate\u2010induced immunosuppression. In vivo studies demonstrate that this dual\u2010regulation strategy effectively inhibits tumor growth, downregulates metastasis\u2010related factors (amphiregulin (AREG), ATP\u2010binding cassette sub\u2010family 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.\n                  <\/jats:p>","DOI":"10.1002\/adhm.71659","type":"journal-article","created":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T04:43:06Z","timestamp":1787978586000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted Lactic Acid Regulation via Engineered Exosomes for Synergistic Metabolic and Photodynamic Tumor Therapy"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-9855-4405","authenticated-orcid":false,"given":"Sisi","family":"Zhou","sequence":"first","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine Jiangsu Engineering Laboratory of Smart Carbon\u2010Rich Materials and Device Key Laboratory of Environmental Medicine Engineering Ministry of Education School of Chemistry and Chemical Engineering Analysis and Testing Center Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-3127-2497","authenticated-orcid":false,"given":"Yu","family":"Cao","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine Jiangsu Engineering Laboratory of Smart Carbon\u2010Rich Materials and Device Key Laboratory of Environmental Medicine Engineering Ministry of Education School of Chemistry and Chemical Engineering Analysis and Testing Center Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9561-9911","authenticated-orcid":false,"given":"Xianbiao","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Materials and Chemical Engineering Anhui Jianzhu University  Hefei China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4686-5291","authenticated-orcid":false,"given":"Songqin","family":"Liu","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Key Laboratory of Critical Care Medicine Jiangsu Engineering Laboratory of Smart Carbon\u2010Rich Materials and Device Key Laboratory of Environmental Medicine Engineering Ministry of Education School of Chemistry and Chemical Engineering Analysis and Testing Center Southeast University  Nanjing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2011.02.013"},{"key":"e_1_2_10_3_1","first-page":"916","article-title":"High Lactate Levels Predict Likelihood of Metastases, Tumor Recurrence, and Restricted Patient Survival in Human Cervical Cancers","volume":"60","author":"Walenta 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