This study developed an ultrasound-responsive nanobubble system co-delivering miR-195-5p and shikonin, synergistically remodeling the hepatocellular carcinoma immunosuppressive tumor microenvironment (TIME) through immunogenic cell death (ICD) and PD-L1 inhibition, thereby significantly improving PD-1 blockade immunotherapy efficacy. This platform effectively addresses shikonin's poor solubility and systemic toxicity issues while enhancing tumor targeting accuracy and safety.
Literature Overview
This article titled 'Ultrasound-activated miR-195-5p/shikonin nanobubbles remodel immunosuppressive microenvironment via immunogenic cell death to potentiate PD-1/PD-L1 blockade in hepatocellular carcinoma' published in Materials Today Bio presents a novel ultrasound-responsive nanobubble delivery platform. The system utilizes miR-195-5p and shikonin (SK) synergism to activate immunogenic cell death (ICD) and suppress PD-L1 expression, enhancing antitumor immune responses. The study validates tumor targeting specificity, stability, and therapeutic synergy in murine models, offering new strategies for hepatocellular carcinoma immunotherapy.
Background Knowledge
Hepatocellular carcinoma (HCC) ranks third among cancer-related mortalities globally. While PD-1/PD-L1 immune checkpoint blockade has achieved clinical progress, objective response rates remain below 20% due to TIME factors including regulatory T cell infiltration, immune checkpoint molecule expression, and immunological tolerance. Immunogenic cell death (ICD) is characterized by damage-associated molecular patterns (DAMPs) release (CRT, ATP, HMGB1), promoting dendritic cell maturation and T cell activation. However, shikonin's clinical application is limited by poor aqueous solubility and systemic toxicity. miR-195-5p has been confirmed to target PD-L1 expression and enhance antitumor immunity. Current delivery systems for miRNA or SK alone face challenges in stability, targeting precision, and controlled release. Combining active targeting with ultrasound-responsive release through nanobubbles (NBs) offers potential for localized delivery of SK and miR-195-5p to synergize ICD and PD-L1 blockade.
Research Methods and Experiments
The research team constructed ultrasound-responsive miR-195-5p/SK-NBs by co-loading miR-195-5p and SK into lipid nanobubbles. Tumor-specific accumulation was achieved through passive targeting (EPR effect) and active targeting (cationic lipid-mediated). Ultrasound irradiation triggered localized release of both agents. Multiple techniques including qPCR, Western blot, flow cytometry, fluorescence microscopy, ELISA, and immunohistochemistry were employed to evaluate PD-L1 downregulation, ICD activation, and immune cell proliferation/infiltration.
Key Conclusions and Perspectives
Research Significance and Prospects
This study provides a novel ultrasound-responsive nanoplatform that synergizes PD-L1 silencing and ICD induction for effective HCC treatment. Future work should optimize drug loading capacity, release kinetics, and in vivo stability for validation in non-human primate models. The platform's design principles offer broad applicability across tumor immunotherapies including pancreatic cancer and melanoma.
Conclusion
This research successfully developed an ultrasound-responsive miR-195-5p/SK-NBs nanodelivery system that effectively activates ICD and suppresses PD-L1 expression both in vitro and in vivo, synergistically enhancing anti-PD-1 immunotherapy. Utilizing UTMD technology, the platform achieves tumor-specific delivery, significantly improving TIME and antitumor immune responses. The study establishes new paradigms for HCC targeted immunotherapy and provides a reference platform for combination treatments in refractory tumors.
