A tumor-targeting gambogic acid-loaded nanovaccine reprograms the tumor microenvironment for enhanced cancer immunotherapy.

Nanovaccines for co-delivering antigens and adjuvants have demonstrated certain efficacy in cancer immunotherapy. However, these vaccines are challenged by poor biocompatibility, insufficient targeting ability, and attenuated performance in the immunosuppressive tumor microenvironment (TME). In this study, we successfully constructed a cancer cell membrane (CCM)-coated nanovaccine loaded with an active component from traditional Chinese medicine, gambogic acid (GA), using a magnesium/aluminum layered double hydroxide (LDH) as the functional carrier (CCM-LDH@GA). CCM serves as a source of tumor-associated antigens, endowing the nanovaccine with homologous targeting ability and a prolonged circulation time, while the LDH carrier enables efficient loading of GA and facilitates pH-responsive release in the acidic TME, thereby enhancing the therapeutic efficacy of GA while effectively addressing its drawbacks, which include poor solubility, low tumor selectivity, and potential toxicity. In vivo studies in a CT26 colorectal cancer mouse model showed that CCM-LDH@GA exhibits efficient tumor targeting and remodels the immunosuppressive TME by promoting dendritic cell maturation, inhibiting macrophage M2 polarization, and activating T cells, thereby inducing a robust antitumor response. In addition, the combination of the nanovaccine with immune checkpoint inhibitors achieves synergistic therapeutic efficacy with a favorable safety profile. In conclusion, this study presents a robust nanovaccine platform capable of eliciting potent antitumor immunity, demonstrating significant potential for clinical translation in cancer immunotherapy.