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Biologically, GC is associated with multiple barriers to therapeutic response including gastric mucosal layer, acidic tumor microenvironment (TME), high accumulation of extracellular matrix (ECM) components, and limited penetration depth of anticancer drugs into tumor tissue. Furthermore, inherent or acquired drug resistance associated with drug efflux transporters, deregulated autophagy, tumor heterogeneity, and cell survival pathways severely compromise treatment response. Nanotechnology has been widely used to develop next-generation nanotherapeutic delivery systems to overcome these biological barriers. Currently available nanoplatforms such as liposomes, polymeric nanoparticles, dendrimers, and inorganic nanocarriers have improved drug loading capacity, aqueous solubility, circulation time stability, tumor-targeted delivery, and sustained release of chemotherapeutics. Smart and stimuli-responsive nanocarriers can also take advantage of pathological hallmarks of tumors including low pH, redox potential, and overexpressed enzymes for enhanced selective delivery to the tumor site. Nanotherapeutics have also shown promise for co-delivery of multiple therapeutic agents to overcome drug resistance, manipulation of TME, and suppression of autophagy and apoptosis signaling pathways associated with drug resistance. This review discusses recent advances in nanotherapeutics for GC including approaches to overcome biological barriers and drug resistance and highlights translational gaps for clinical development.<\/jats:p>","DOI":"10.3390\/cells15100850","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T12:15:07Z","timestamp":1778156107000},"page":"850","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Overcoming Biological Barriers and Drug Resistance Through Next-Generation Nanotherapeutic Delivery in Gastric Cancer"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6649-3694","authenticated-orcid":false,"given":"Md Ataur","family":"Rahman","sequence":"first","affiliation":[{"name":"Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maroua","family":"Jalouli","sequence":"additional","affiliation":[{"name":"Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2170-1303","authenticated-orcid":false,"given":"Abdel Halim","family":"Harrath","sequence":"additional","affiliation":[{"name":"Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-7569-6480","authenticated-orcid":false,"given":"Jinwon","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo Jeong","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2470-4613","authenticated-orcid":false,"given":"Sohyun","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bum-Sang","family":"Shim","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-7916-5743","authenticated-orcid":false,"given":"Amama","family":"Rani","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8678-156X","authenticated-orcid":false,"given":"Bonglee","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pathology, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Korean Medicine-Based Drug Repositioning Cancer Research Center, College of Korean Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Shin, W.S., Xie, F., Chen, B., Yu, P., Yu, J., To, K.F., and Kang, W. 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