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Blocking the PI3K\/mTOR signaling pathway has been recently proved as a new strategy to improve sensitivity to chemotherapy and immunotherapy. Herein, glutathione (GSH)\u2010sensitive nanoparticles (PSMA\u2010NP\/BEZ) are developed that can target prostate\u2010specific membrane antigen (PSMA), loaded with PI3K\/mTOR dual inhibitor prodrug BEZ235. BEZ235 can be released from PSMA\u2010NP\/BEZ in response to elevated GSH levels in prostate cancer tissues, inhibiting the PI3K\/AKT\/mTOR pathway and impairing downstream cellular functions such as cell proliferation, DNA repair, and protein synthesis. When combined with paclitaxel, PSMA\u2010NP\/BEZ could reduce drug efflux by downregulating P\u2010glycoprotein expression in cancer cells, thus enhancing the sensitivity to chemotherapy. Furthermore, PSMA\u2010NP\/BEZ could impair the immunosuppressive functions of myeloid\u2010derived suppressor cells and reshape the \u201ccold\u201d immune microenvironment in prostate cancer, enhancing immunotherapeutic efficacy and including long\u2010term immune memory against tumor recurrence. PSMA\u2010NP\/BEZ serves a safe and promising strategy to improve the efficacy of chemotherapy and immunotherapy in advanced prostate cancer.<\/jats:p>","DOI":"10.1002\/adma.202415322","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T08:49:03Z","timestamp":1748335743000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["PSMA\u2010Targeted Nanoparticles with PI3K\/mTOR Dual Inhibitor Downregulate P\u2010Glycoprotein and Inactivate Myeloid\u2010Derived Suppressor Cells for Enhanced Chemotherapy and Immunotherapy in Prostate Cancer"],"prefix":"10.1002","volume":"37","author":[{"given":"Lu","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Urology National Cancer Center\/National Clinical Research Center for Cancer\/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing 100021 P. R. 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