2. Academic Validation
  3. Immunosuppressive-responsive hydrogel for self-regulated drug release and tumor microenvironment reprogramming

Immunosuppressive-responsive hydrogel for self-regulated drug release and tumor microenvironment reprogramming

  • J Control Release. 2026 Apr 10:392:114698. doi: 10.1016/j.jconrel.2026.114698.
Yuxin Wang 1,  Qinghe Wang 1,  Xiyue Xu 1,  Haixuan Yuan 2,  Yexin Hu 1,  Feng Feng 3,  Fulei Liu 4,  Jingwei Xue 5,  Wenyuan Liu 6,  Lingfei Han 7
Affiliations

Affiliations

  • 1 Department of pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Taizhou University, Taizhou 225300, China; School of Pharmacy, Nanjing Medical University, Nanjing 211166, China; Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing 211198, China.
  • 4 Tumor Precise Intervention and Translational Medicine Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian 271000, China.
  • 5 Tumor Precise Intervention and Translational Medicine Laboratory, The Affiliated Taian City Central Hospital of Qingdao University, Taian 271000, China. Electronic address: [email protected].
  • 6 Department of pharmacy, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
  • 7 Department of pharmacy, China Pharmaceutical University, Nanjing 211198, China. Electronic address: [email protected].
PMID: 41692045 DOI: 10.1016/j.jconrel.2026.114698
Abstract

The tumor immunosuppressive microenvironment (TIME) critically suppresses antitumor immunity and fosters tumor growth and metastasis, leading to treatment resistance and poor prognosis. Inhibition of the upstream immunosuppressive regulator transforming growth factor-β (TGF-β) is an effective approach but systemic blockade should be avoided. To address this, an intelligent and injectable thermo-responsive hydrogel delivery system (LY@CNSG) constructed from cyclodextrin nanosponges and poly(N-isopropylacrylamide) was developed, in response to immunosuppressive prostaglandin E2 (PGE2) levels for autonomously controlling the release of LY2109761 (LY, a TGF-β inhibitor) based on competitive host-guest interaction. In triple-negative breast Cancer models, photodynamic therapy combined with LY@CNSG significantly inhibited tumor growth and lung metastasis while enhancing antitumor immune activity. Furthermore, by integrating nitric oxide (NO)-responsive fluorescent probes, we created an integrated hydrogel platform, CYNH2-LY@CNSG, for simultaneous immunomodulator delivery and immune signaling molecule monitoring, providing a novel insight for biomarker monitoring and a more precise immunotherapy paradigm.

Keywords

Antitumor immunity; Cyclodextrin nanosponges; Immunosuppressive-responsive; In situ monitoring; Injectable thermo-responsive hydrogel; NO fluorescent probe; Self-regulated drug release; TGF-β blockade.

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