Oral artificial microbio-vaccine triggers synergistic immunogenic cell death induction and tumor microenvironment remodeling for liver cancer therapy

Artificial cellular systems, engineered to mimic biological functions, offer a promising platform for advanced drug delivery and immunotherapy. Translating such systems into effective oral tumor vaccines, however, remains challenging due to the harsh gastrointestinal environment, inefficient immune activation, and the toxicity of potent immunogenic agents. To overcome these barriers, we engineered an oral artificial micro bio-vaccine via a hierarchical assembly strategy. Triptolide (TP), an immunogenic cell death inducer, was co-assembled with glycyrrhizic acid (GA), an immunomodulator, into a nanodetoxifying core to facilitate efficient loading into hollow Saccharomyces cerevisiae microcapsules (YC), forming the final aggregate (TP/GA-NYPs). This rational design leverages the YC for gastric protection and gut mucosa-targeting, while the Chitosan shell ensures robust encapsulation. Crucially, the TP/GA core demonstrates a synergistic interplay, in which TP potently induces immunogenic cell death, while GA concurrently remodels the immunosuppressive tumor microenvironment by suppressing metastasis-related markers and enhancing immunostimulatory cytokine profiles. This spatiotemporally coupled action within a single oral aggregate elicits robust intestinal mucosal and systemic immunity, effectively suppressing liver cancer progression and metastasis while mitigating the systemic toxicity of TP. This work highlights the therapeutic potential of functional aggregates in orchestrating synergistic anti-tumor immunity and offers a versatile platform for oral immunotherapy.