{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T04:58:03Z","timestamp":1781672283897,"version":"3.54.5"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Multidrug resistance (MDR) critically limits doxorubicin (Dox) efficacy in glioma. To overcome this, we constructed a folic acid receptor (FAR)-targeted liposomal system for codelivering Dox and curcumin (Cur).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Dox\/Cur-Lip@FA was prepared using the film hydration-sonication method. The physicochemical properties (size, zeta potential, encapsulation efficiency, and drug release) were characterized. The studies assessed P-gp modulation and cellular uptake in Dox-resistant C6 cells, as well as\n                      <jats:italic>in vivo<\/jats:italic>\n                      efficacy in xenograft models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The FA ligand enabled selective tumor targeting by binding to overexpressed FAR, while Cur enhanced Dox efficacy by downregulating P-gp-mediated drug efflux. Dox\/Cur-Lip@FA exhibited a uniform size of 112.5 \u00b1 3.8 nm, a zeta potential of -7.85 \u00b1 0.62 mV, high dual-drug EE% (Dox: 91.32 \u00b1 3.95%; Cur: 90.87 \u00b1 4.21%), and sustained release kinetics.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , targeted liposomes achieved 3.56-fold higher cellular uptake in Dox-res-C6 cells compared to non-targeted formulations. In an\n                      <jats:italic>in vitro<\/jats:italic>\n                      BBB model, FA modification significantly enhanced transendothelial transport, suggesting potential for brain delivery.\n                      <jats:italic>In vivo<\/jats:italic>\n                      , Dox\/Cur-Lip@FA induced a 71.19% reduction in tumor volume, significantly outperforming free drugs and non-targeted liposomes. Mechanistic analysis confirmed that Cur effectively suppressed P-gp expression, thereby restoring Dox sensitivity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This FA-functionalized codelivery system combines active targeting with MDR reversal, showing improved cellular uptake\n                      <jats:italic>in vitro<\/jats:italic>\n                      and antitumor efficacy in subcutaneous xenografts, with potential for BBB penetration as suggested by\n                      <jats:italic>in vitro<\/jats:italic>\n                      models.\n                    <\/jats:p>\n                  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