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An immunosuppressive tumor microenvironment (TME) and dysregulation of the polycomb ring finger oncogene BMI1 are potential reasons for the failure. Herein, to promote immunotherapeutic efficacy against HNSCC, an injectable nanocomposite hydrogel is developed with a polymer framework (PLGA\u2010PEG\u2010PLGA) that is loaded with both imiquimod encapsulated CaCO\n                    <jats:sub>3<\/jats:sub>\n                    nanoparticles (RC) and cancer cell membrane (CCM)\u2010coated mesoporous silica nanoparticles containing a peptide\u2010based proteolysis\u2010targeting chimeras (PROTAC) for BMI1 and paclitaxel (PepM@PacC). Upon injection, this nanocomposite hydrogel undergoes in situ gelation, after which it degrades in the TME over time, releasing RC and PepM@PacC nanoparticles to respectively perform immunotherapy and chemotherapy. Specifically, the RC particles selectively manipulate tumor\u2010associated macrophages and dendritic cells to activate a T\u2010cell immune response, while CCM\u2010mediated homologous targeting and endocytosis delivers the PepM@PacC particles into cancer cells, where endogenous glutathione promotes disulfide bond cleavage to release the PROTAC peptide for BMI1 degradation and frees the paclitaxel from the particle pores to elicit apoptosis meanwhile enhance immunotherapy. Thus, the nanocomposite hydrogel, which is designed to exploit multiple known vulnerabilities of HNSCC, succeeds in suppressing both growth and metastasis of HNSCC.\n                  <\/jats:p>","DOI":"10.1002\/adma.202210787","type":"journal-article","created":{"date-parts":[[2023,1,19]],"date-time":"2023-01-19T14:08:22Z","timestamp":1674137302000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":111,"title":["A Physiologically Responsive Nanocomposite Hydrogel for Treatment of Head and Neck Squamous Cell Carcinoma via Proteolysis\u2010Targeting Chimeras Enhanced Immunotherapy"],"prefix":"10.1002","volume":"35","author":[{"given":"Yaping","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial\u2010Head Neck Oncology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine College of Stomatology Shanghai Jiao Tong University National Center for Stomatology National Clinical Research Center for Oral Diseases Shanghai Key Laboratory of Stomatology Shanghai Research Institute of Stomatology  Shanghai 200011 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowei","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering Shaanxi Key Laboratory of Energy Chemical Process Intensification Institute of Polymer Science in Chemical Engineering School of Chemical Engineering and Technology Xi'an Jiaotong University  Xi'an 710049 P. R. China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guizhu","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial\u2010Head Neck Oncology Shanghai Ninth People's Hospital Shanghai Jiao Tong University School of Medicine College of Stomatology Shanghai Jiao Tong University National Center for Stomatology National Clinical Research Center for Oral Diseases Shanghai Key Laboratory of Stomatology Shanghai Research Institute of Stomatology  Shanghai 200011 P. R. 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