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However, uncertain loading ratio, release sequence, and spatiotemporal distribution of drugs hinder their synergistic therapeutic effects and clinical applications. In this work, a tumor microenvironments\u2010adapted composite consisting of a thermosensitive hydrogel and a reactive oxygen species (ROS)\u2010responsive nanogel is developed for precisely sequential drug release to enhance molecularly targeted therapy and amplify immune activation. LY3200882 (LY), a selective transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2) inhibitor, is encapsulated in the ROS\u2010responsive nanogel and dispersed uniformly with regorafenib (REG) in a thermosensitive hydrogel (Gel\/(REG+NG\/LY)). After in situ administration, REG is preferentially released from the hydrogel to inhibit tumor growth and promote ROS generation, which triggers the subsequent on\u2010demand release of LY from the nanogel. LY contributes to preventing the epithelial\u2013mesenchymal transition and immune escape of tumor cells induced by elevated TGF\u2010\u03b2. In subcutaneous and orthotopic colorectal tumor bearing mouse models, Gel\/(REG+NG\/LY) effectively inhibits tumor growth and liver metastases by increasing the tumor infiltration of CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, reducing the recruitment of tumor\u2010associated macrophages and myeloid\u2010derived suppressor cells, and promoting the polarization of macrophages from M2 to M1 type, indicating the significant potential in improving the prognosis of advanced cancer patients.\n                  <\/jats:p>","DOI":"10.1002\/adma.202200449","type":"journal-article","created":{"date-parts":[[2022,3,15]],"date-time":"2022-03-15T14:38:20Z","timestamp":1647355100000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":143,"title":["A Tumor Microenvironments\u2010Adapted Polypeptide Hydrogel\/Nanogel Composite Boosts Antitumor Molecularly Targeted Inhibition and Immunoactivation"],"prefix":"10.1002","volume":"34","author":[{"given":"Zhongmin","family":"Li","sequence":"first","affiliation":[{"name":"Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education National\u2010Local Joint Engineering Laboratory of Animal Models for Human Diseases Jilin University  1 Xinmin Street Changchun 130061 P. 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