{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T19:18:40Z","timestamp":1792523920117,"version":"4.5.0"},"reference-count":38,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T00:00:00Z","timestamp":1774396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002858","name":"China Postdoctoral Science Foundation","doi-asserted-by":"publisher","award":["2024M763334"],"award-info":[{"award-number":["2024M763334"]}],"id":[{"id":"10.13039\/501100002858","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2024M763334"],"award-info":[{"award-number":["2024M763334"]}],"id":[{"id":"https:\/\/ror.org\/0426zh255","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biosensors"],"abstract":"<jats:p>In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) and the fibrotic stroma generate form a dense stromal barrier that restricts the intratumoural exposure and spatial distribution of oxaliplatin. To enable local stromal remodelling of this pathological stromal compartment, we selected fibroblast activation protein (FAP) as a stromal target and co-assembled two amphiphilic conjugates, oncoFAP and retinoic acid (RA), into an FAP-directed RA nanoformulation termed LRAFAP. LRAFAP exhibited a uniform size distribution (107.1 \u00b1 5.8 nm), remained stable for at least 7 d at 37 \u00b0C in PBS or serum-containing PBS, and showed accelerated esterase-responsive release. In a TGF-\u03b2-induced CAF-like model, LRAFAP markedly suppressed the expression of CAF activation-associated markers, reducing Fap and Acta2 mRNA levels by approximately 70% and 60%, respectively. In vivo, LRAFAP showed enhanced accumulation in CAF-enriched tumours and an increase in intratumoural oxaliplatin levels of approximately 2.5-fold relative to oxaliplatin alone. LRAFAP also reduced collagen deposition and CAF activation markers, and enhanced the antitumour efficacy of oxaliplatin while maintaining good tolerability. Collectively, these findings indicate that LRAFAP promotes local stromal remodelling and improves intratumoural oxaliplatin exposure, thereby enhancing the efficacy of oxaliplatin-based chemotherapy in CRC.<\/jats:p>","DOI":"10.3390\/bios16040189","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T13:37:15Z","timestamp":1774532235000},"page":"189","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["FAP-Anchored Retinoic Acid Nanoparticles for Stromal Reprogramming and Enhanced Intratumoral Oxaliplatin Delivery in Fibrotic Colorectal Tumours"],"prefix":"10.3390","volume":"16","author":[{"given":"Haixia","family":"Wang","sequence":"first","affiliation":[{"name":"Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Can","family":"Xu","sequence":"additional","affiliation":[{"name":"College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Xie","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohe","family":"Chu","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, Hangzhou 310014, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wang","sequence":"additional","affiliation":[{"name":"Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,25]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1016\/j.annonc.2020.06.022","article-title":"Localised colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Argiles","year":"2020","journal-title":"Ann. Oncol."},{"key":"ref_3","first-page":"2343","article-title":"Oxaliplatin, Fluorouracil, and Leucovorin as Adjuvant Treatment for Colon Cancer","volume":"23","author":"Boni","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.annonc.2022.10.003","article-title":"Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up","volume":"34","author":"Cervantes","year":"2023","journal-title":"Ann. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.trecan.2018.02.005","article-title":"Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside","volume":"4","author":"Stylianopoulos","year":"2018","journal-title":"Trends Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3325","DOI":"10.1200\/JCO.20.01399","article-title":"Prevention and Management of Chemotherapy-Induced Peripheral Neuropathy in Survivors of Adult Cancers: ASCO Guideline Update","volume":"38","author":"Loprinzi","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1016\/j.drup.2011.08.001","article-title":"Epigenetics and chemoresistance in colorectal cancer: An opportunity for treatment tailoring and novel therapeutic strategies","volume":"14","author":"Crea","year":"2011","journal-title":"Drug Resist. Updat."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/j.jcmgh.2024.01.013","article-title":"Fibroblasts in Orchestrating Colorectal Tumorigenesis and Progression","volume":"17","author":"Abudukelimu","year":"2024","journal-title":"Cell Mol. Gastroenterol. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3833","DOI":"10.1158\/0008-5472.CAN-12-4521","article-title":"Coevolution of solid stress and interstitial fluid pressure in tumors during progression: Implications for vascular collapse","volume":"73","author":"Stylianopoulos","year":"2013","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4692","DOI":"10.1038\/s41467-018-06654-8","article-title":"TGF-beta-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure","volume":"9","author":"Chakravarthy","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1136\/gutjnl-2019-319200","article-title":"STAT3 activation through IL-6\/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis","volume":"69","author":"Heichler","year":"2020","journal-title":"Gut"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Mezzapelle, R., Leo, M., Caprioglio, F., Colley, L.S., Lamarca, A., Sabatino, L., Colantuoni, V., Crippa, M.P., and Bianchi, M.E. (2022). CXCR4\/CXCL12 Activities in the Tumor Microenvironment and Implications for Tumor Immunotherapy. Cancers, 14.","DOI":"10.3390\/cancers14092314"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/j.ccr.2012.01.007","article-title":"Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma","volume":"21","author":"Provenzano","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1038\/ncomms3516","article-title":"Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels","volume":"4","author":"Chauhan","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"46140","DOI":"10.1038\/srep46140","article-title":"Tranilast-induced stress alleviation in solid tumors improves the efficacy of chemo- and nanotherapeutics in a size-independent manner","volume":"7","author":"Papageorgis","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1038\/nrc1893","article-title":"Drug penetration in solid tumours","volume":"6","author":"Minchinton","year":"2006","journal-title":"Nat. Rev. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.jconrel.2024.02.014","article-title":"In vivo activation of FAP-cleavable small molecule-drug conjugates for the targeted delivery of camptothecins and tubulin poisons to the tumor microenvironment","volume":"367","author":"Bocci","year":"2024","journal-title":"J. Control Release"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.ccr.2014.04.005","article-title":"Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival","volume":"25","author":"Ozdemir","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41392-020-00436-9","article-title":"Targeting TGFbeta signal transduction for cancer therapy","volume":"6","author":"Liu","year":"2021","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Panico, S., Capolla, S., Bozzer, S., Toffoli, G., Dal Bo, M., and Macor, P. (2022). Biological Features of Nanoparticles: Protein Corona Formation and Interaction with the Immune System. Pharmaceutics, 14.","DOI":"10.3390\/pharmaceutics14122605"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"4366","DOI":"10.1038\/s41467-024-48838-5","article-title":"Rediscovery of mononuclear phagocyte system blockade for nanoparticle drug delivery","volume":"15","author":"Zelepukin","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.abb.2004.05.004","article-title":"Regulation of alpha 2(I) collagen expression in stellate cells by retinoic acid and retinoid X receptors through interactions with their cofactors","volume":"428","author":"Wang","year":"2004","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S0006-2952(03)00390-3","article-title":"Regulation of pancreatic stellate cell function in vitro: Biological and molecular effects of all-trans retinoic acid","volume":"66","author":"Jaster","year":"2003","journal-title":"Biochem. Pharmacol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e2101460","DOI":"10.1002\/smll.202101460","article-title":"Small-Molecule Prodrug Nanoassemblies: An Emerging Nanoplatform for Anticancer Drug Delivery","volume":"17","author":"Li","year":"2021","journal-title":"Small"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1158\/2767-9764.CRC-23-0073","article-title":"Desmoplastic Reaction Associates with Prognosis and Adjuvant Chemotherapy Response in Colorectal Cancer: A Multicenter Retrospective Study","volume":"3","author":"Hu","year":"2023","journal-title":"Cancer Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1002\/ijc.33947","article-title":"Cancer-associated fibroblasts at the unfavorable desmoplastic stroma promote colorectal cancer aggressiveness: Potential role of ADAM9","volume":"150","author":"Ao","year":"2022","journal-title":"Int. J. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/s41571-018-0007-1","article-title":"Targeting the tumour stroma to improve cancer therapy","volume":"15","author":"Valkenburg","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/nrc1456","article-title":"High interstitial fluid pressure\u2014An obstacle in cancer therapy","volume":"4","author":"Heldin","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1146\/annurev-bioeng-071813-105259","article-title":"The role of mechanical forces in tumor growth and therapy","volume":"16","author":"Jain","year":"2014","journal-title":"Annu. Rev. Biomed. Eng."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15101","DOI":"10.1073\/pnas.1213353109","article-title":"Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors","volume":"109","author":"Stylianopoulos","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1016\/j.cell.2009.10.027","article-title":"Matrix crosslinking forces tumor progression by enhancing integrin signaling","volume":"139","author":"Levental","year":"2009","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e194003","DOI":"10.1148\/rycan.2019194003","article-title":"(68)Ga FAPI PET\/CT: Tracer Uptake in 28 Different Kinds of Cancer","volume":"1","author":"Hathi","year":"2019","journal-title":"Radiol. Imaging Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4740","DOI":"10.1158\/1078-0432.CCR-23-1983","article-title":"Fibroblast Activation Protein-Targeted Radioligand Therapy with 177Lu-EB-FAPI for Metastatic Radioiodine-Refractory Thyroid Cancer: First-in-Human, Dose-Escalation Study","volume":"29","author":"Fu","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e2101852118","DOI":"10.1073\/pnas.2101852118","article-title":"An ultra-high-affinity small organic ligand of fibroblast activation protein for tumor-targeting applications","volume":"118","author":"Millul","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"113888","DOI":"10.1016\/j.jconrel.2025.113888","article-title":"In vivo FAP-CAR macrophages enhance chemotherapy and immunotherapy against pancreatic cancer by removing the fibrosis barrier","volume":"384","author":"Wang","year":"2025","journal-title":"J. Control. Release"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1084\/jem.20130110","article-title":"Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia","volume":"210","author":"Tran","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4841","DOI":"10.1038\/s41467-020-18636-w","article-title":"Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer","volume":"11","author":"Kocher","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"12630","DOI":"10.1038\/ncomms12630","article-title":"ATRA mechanically reprograms pancreatic stellate cells to suppress matrix remodelling and inhibit cancer cell invasion","volume":"7","author":"Chronopoulos","year":"2016","journal-title":"Nat. Commun."}],"container-title":["Biosensors"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-6374\/16\/4\/189\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T12:34:20Z","timestamp":1775565260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-6374\/16\/4\/189"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,25]]},"references-count":38,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["bios16040189"],"URL":"https:\/\/doi.org\/10.3390\/bios16040189","relation":{},"ISSN":["2079-6374"],"issn-type":[{"value":"2079-6374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,25]]}}}