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However, systematical administration of protein drugs may cause serious side effects. In order to prepare a new promising hydrophilic drugs carrier, we constructed a PEGylated hyaluronic acid nanogel (NI-MAHA-PEG nanogel) with hypoxia and enzymatic responsiveness, which can selectively release hydrophilic drugs interleukin-12 (IL-12) on demand in a tumor microenvironment. We observed that release of IL-12 from nanogels by hypoxia-responsive stimulation, nanogels have anti-tumor effects on melanoma. Compared with physiological conditions, the IL-12 release rate has achieved remarkable growth under hypoxic conditions. Similarly, the drug release rate increased significantly with the addition of 500 U ml\n                    <jats:sup>\u22121<\/jats:sup>\n                    hyaluronidase. We provide a novel strategy to allow efficient delivery, on-demand release, and enhanced access of proteins to hypoxic tumor regions. The rational design of this nanogels drug delivery system can further explore the use of various drugs to treat many cancers.\n                  <\/jats:p>","DOI":"10.1088\/1361-6528\/abcdcc","type":"journal-article","created":{"date-parts":[[2020,11,25]],"date-time":"2020-11-25T17:30:28Z","timestamp":1606325428000},"page":"095107","update-policy":"https:\/\/doi.org\/10.1088\/crossmark-policy","source":"Crossref","is-referenced-by-count":21,"title":["Hypoxia-responsive nanogel as IL-12 carrier for anti-cancer therapy"],"prefix":"10.1088","volume":"32","author":[{"given":"Changhuan","family":"Zhang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qinghua","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenghu","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jilong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Su","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5137-8615","authenticated-orcid":false,"given":"Junjie","family":"Deng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"266","published-online":{"date-parts":[[2020,12,10]]},"reference":[{"key":"nanoabcdccbib1","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.cell.2020.05.028","type":"journal-article","article-title":"Developing covalent protein drugs via proximity-enabled reactive therapeutics","volume":"182","author":"Li","year":"2020","journal-title":"Cell"},{"key":"nanoabcdccbib2","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1200\/JCO.2016.67.4887","type":"journal-article","article-title":"Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: primary results from the phase III MARIANNE study","volume":"35","author":"Perez","year":"2017","journal-title":"J. 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All rights, including for text and data mining, AI training, and similar technologies, are reserved.","name":"copyright_information","label":"Copyright Information"},{"value":"2020-09-07","name":"date_received","label":"Date Received","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2020-11-25","name":"date_accepted","label":"Date Accepted","group":{"name":"publication_dates","label":"Publication dates"}},{"value":"2020-12-10","name":"date_epub","label":"Online publication date","group":{"name":"publication_dates","label":"Publication dates"}}]}}