{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:47:36Z","timestamp":1785422856860,"version":"3.56.0"},"posted":{"date-parts":[[2026,7,15]]},"group-title":"Bioengineering","reference-count":51,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T00:00:00Z","timestamp":1784073600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R44CA265751"],"award-info":[{"award-number":["R44CA265751"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R44CA265752"],"award-info":[{"award-number":["R44CA265752"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R44CA285233"],"award-info":[{"award-number":["R44CA285233"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Women's Health Circle of Giving at OHSU"},{"name":"Frohnmayer Hicks Sciarretta Cancer Research Scholar award from the Knight Cancer Institute"},{"name":"Joe W. and Jane E. Gray Professorship Fund"},{"award":["FRB660044\/0240"],"award-info":[{"award-number":["FRB660044\/0240"]}],"id":[{"id":"https:\/\/ror.org\/03b5p6e80","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Low response rates to immune checkpoint inhibitors (ICIs) in solid tumors are often driven by insufficient tumor-infiltrating CD8\u207a T cells and immunosuppressive tumor microenvironment (TME). Although interleukin-2 (IL-2) potently expands and activates CD8\u207a T cells, its clinical use is limited by rapid clearance, dose-limiting toxicity, and regulatory T cell (T\n                  <jats:sub>reg<\/jats:sub>\n                  ) stimulation. Engineered IL-2 variants have not yet achieved meaningful clinical efficacy. Here, polymer-modified mesoporous silica nanoparticles displaying dense, unmodified wild-type IL-2 on their surface (IL2-NP) are developed, conferring proteolytic stability and tumor retention. IL2-NP enables avidity-mediated CD8\u207a T cell binding and enhances proliferation and effector function without increased T\n                  <jats:sub>reg<\/jats:sub>\n                  binding or proliferation.\n                <\/jats:p>\n                <jats:p>\n                  Intratumoral IL2-NP expands CD8\u207a T cells, increases CD8\u207a\/T\n                  <jats:sub>reg<\/jats:sub>\n                  ratios, and reprograms TME through dendritic cell activation and M1-like macrophage polarization. IL2-NP induces regression of both treated and untreated distant colorectal tumors in a CD8\u207a T cell-dependent manner. IL2-NP synergizes with ICIs and leads to complete tumor regression and immunological memory that protect against rechallenge. Treatment is well tolerated, with strong efficacy also observed in triple-negative breast and metastatic ovarian cancer models.\n                <\/jats:p>\n                <jats:p>Overall, intratumoral IL2-NP elicits robust systemic antitumor immunity, offering a promising strategy to enhance ICIs, cancer vaccines, and adoptive T-cell therapies.<\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphical abstract<\/jats:title>\n                  <jats:p>This work introduces a nanoparticle platform that overcomes major shortcomings of IL-2 immunotherapy by presenting wild-type IL-2 at high density on the nanoparticle surface, thereby increasing binding avidity to effector T cells. The resulting IL-2 nanoparticles enhance cytotoxic T cell expansion, reprogram the tumor microenvironment, and augment responses to immune checkpoint blockade to achieve robust ant-tumor immune response in mouse tumor models.<\/jats:p>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"738558v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.64898\/2026.07.14.738558","type":"posted-content","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T11:55:18Z","timestamp":1784116518000},"source":"Crossref","is-referenced-by-count":0,"title":["High-Density Wild-Type IL-2 Nanoparticles Preferentially Enhance CD8\u207a T-Cell Expansion and Reprogram the Tumor Microenvironment"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9611-4974","authenticated-orcid":false,"given":"Ruijie","family":"Wang","sequence":"first","affiliation":[{"name":"Biomedical Engineering, Oregon Health & Science University, Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6315-0538","authenticated-orcid":false,"given":"Pramod","family":"Kumar","sequence":"additional","affiliation":[{"name":"Biomedical Engineering, Oregon Health & Science University, Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noah A.","family":"Crumrine","sequence":"additional","affiliation":[{"name":"PDX Pharmaceuticals, Inc., Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tongchatra","family":"Watcharawittayakul","sequence":"additional","affiliation":[{"name":"PDX Pharmaceuticals, Inc., Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Wallstrum","sequence":"additional","affiliation":[{"name":"PDX Pharmaceuticals, Inc., Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moataz","family":"Reda","sequence":"additional","affiliation":[{"name":"PDX Pharmaceuticals, Inc., Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0144-9614","authenticated-orcid":false,"given":"Gordon","family":"Mills","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4187-7709","authenticated-orcid":false,"given":"Worapol","family":"Ngamcherdtrakul","sequence":"additional","affiliation":[{"name":"PDX Pharmaceuticals, Inc., Portland, OR"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0989-363X","authenticated-orcid":false,"given":"Wassana","family":"Yantasee","sequence":"additional","affiliation":[{"name":"Biomedical Engineering, Oregon Health & Science University, Portland, OR"},{"name":"PDX Pharmaceuticals, Inc., Portland, OR"},{"name":"Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026071807100576000_2026.07.14.738558v1.1","unstructured":"American Association for Cancer Research. 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