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

Area of Science:

• Biomedical Engineering
• Cancer Research
• Immunotherapy

Background:

• The tumor immunosuppressive microenvironment (TIME) hinders antitumor immunity, promoting cancer growth, metastasis, and treatment resistance.
• Transforming growth factor-β (TGF-β) is a key regulator of the TIME, but systemic inhibition poses risks.
• Developing localized and responsive drug delivery systems is crucial for effective cancer immunotherapy.

Purpose of the Study:

• To develop an intelligent, injectable, thermo-responsive hydrogel system (LY@CNSG) for localized TGF-β inhibitor delivery.
• To achieve autonomous drug release triggered by prostaglandin E2 (PGE2) levels within the tumor microenvironment.
• To create an integrated platform for simultaneous immunomodulator delivery and immune signaling molecule monitoring.

Main Methods:

• Fabrication of a thermo-responsive hydrogel using cyclodextrin nanosponges and poly(N-isopropylacrylamide).
• Incorporation of LY2109761 (a TGF-β inhibitor) into the hydrogel for controlled release via host-guest interactions.
• Integration of nitric oxide (NO)-responsive fluorescent probes into the hydrogel platform (CYNH2-LY@CNSG).
• Evaluation of the system's efficacy in triple-negative breast cancer models, assessing tumor growth, metastasis, and immune response.

Main Results:

• The LY@CNSG hydrogel demonstrated autonomous release of LY2109761 in response to PGE2.
• Combination therapy of photodynamic therapy with LY@CNSG significantly inhibited tumor growth and lung metastasis in vivo.
• The treatment enhanced antitumor immune activity within the tumor microenvironment.
• The CYNH2-LY@CNSG platform enabled simultaneous drug delivery and real-time monitoring of immune signaling molecules.

Conclusions:

• The intelligent hydrogel system effectively targets the tumor immunosuppressive microenvironment by delivering a TGF-β inhibitor in a controlled manner.
• This approach enhances the efficacy of photodynamic therapy and boosts antitumor immunity.
• The integrated platform offers a novel strategy for biomarker monitoring and precision immunotherapy, paving the way for improved cancer treatment paradigms.