{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T08:38:55Z","timestamp":1767947935154,"version":"3.49.0"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T00:00:00Z","timestamp":1767916800000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immunotherapy becoming the focus of contemporary multidisciplinary collaborative research efforts towards advanced hepatocellular carcinoma (HCC).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aims to develop a nanobubble (NB) delivery system designed to co-administer an immunogenic cell death (ICD) inducer, Shikonin (SK), alongside an immune checkpoint inhibitor, miR-497-5p, to enhance the efficacy of the immune response against liver cancer.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      NBs were synthesized through thin-film hydration and mechanical oscillation techniques to encapsulate miR-497 and SK. Comprehensive characterization and pharmacokinetic analyses of the miR-497\/SK-loaded NBs were conducted both\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      . To evaluate the anti-tumor efficacy and immunological activity of this combination therapy, a subcutaneous transplanted tumor model using H22 hepatoma cells was established.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The miR-497\/SK-NBs demonstrated an optimal morphology and size, as well as excellent gene capacity and SK encapsulation. The\n                      <jats:italic>in vivo<\/jats:italic>\n                      anti-tumor effects and mechanisms of SK and miR-497 were assessed in H22 hepatoma transplants model. The miR-497\/SK-NBs group showed the strongest tumor inhibition, with their synergistic immunotherapeutic effect demonstrated through two main mechanisms. Initially, the activation of SK, facilitated by ultrasound, triggered the induction of injury-related molecular patterns, including CRT and HMGB1. This process subsequently activated CD80\n                      <jats:sup>+<\/jats:sup>\n                      CD86\n                      <jats:sup>+<\/jats:sup>\n                      macrophages, thereby enhancing the presentation of tumor antigens. Subsequently, miR-497 contributed to the downregulation of PD-L1 expression in tumor cells. Collectively, these processes elicited a robust systemic anti-tumor immune response and induced apoptosis in tumor cells within murine HCC models.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The study demonstrated that miR-497\/SK-loaded nanobubbles simultaneously boosts ICD and blocks the PD-1\/PD-L1 pathway in immunotherapy. This finding offers a theoretical foundation for the effective eradication of tumor cells and the development of a highly efficient synergistic treatment strategy for HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1672324","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T06:42:03Z","timestamp":1767940923000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing the tumoricidal efficacy of the nanobubbles-mediated PD-L1 inhibition and immunogenic cell death in 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