Enhanced oral nanomedicine utilizing biomineralized oncolytic virus for synergistic gastrointestinal cancer therapy

Oncolytic viruses (OVs) represent a promising nanomedicine strategy for cancer therapy, yet their clinical application-particularly <i>via</i> oral administration-remains challenging due to degradation by digestive enzymes and neutralization by antibodies in the gastrointestinal tract. To address this, we developed a biomineralized cancer membrane-coated oncolytic adenovirus (CaCO₃@CM-OA) with enhanced resistance to enzymatic and immune clearance, significantly improving tumor-targeting efficiency. In colorectal and pancreatic cancer models, this engineered virus induced potent anti-tumor effects <i>via</i> G2/M phase arrest, mediated by p53 phosphorylation and p21 upregulation, while suppressing epithelial-mesenchymal transition (EMT) through downregulation of N-cadherin, vimentin, and α-SMA. Furthermore, the virus triggered multimodal regulated cell death, including mitochondrial apoptosis, autophagy, and necroptosis, accompanied by immunogenic cell death (ICD) markers such as ATP release, calreticulin exposure, and HMGB1 translocation, indicating robust immune activation. Transcriptomic analysis further revealed downregulation of pro-survival genes (e.g., RHBDD2) and modulation of proliferation-related (e.g., ZMYND10, CDC27, ST7) and endocytosis-related (SNX11) genes, elucidating its multifaceted mechanism. This study highlights the potential of biomineralized OVs to overcome oral delivery barriers and enhance therapeutic efficacy in gastrointestinal cancers. By inducing synergistic cell death and immune activation, this strategy provides a foundation for clinical translation and identifies novel molecular targets for future investigation. Our findings underscore the feasibility of engineered oral OV formulations to improve treatment outcomes in intestinal malignancies.