Probiotic-inspired hybrid nanovesicles for enhancing immune checkpoint therapy efficiency via tumor immune microenvironment modulation

Immunologically “cold” tumors, characterized by low immune cells infiltration, represent a significant obstacle to the success of immune checkpoint therapy. Intestinal microbiome therapy has emerged as a potential strategy to overcome this challenge by reprogramming the immune microenvironment. However, its clinical application is constrained by unresolved safety concerns. To address these challenges, we fused Escherichia coli -secreted outer membrane vesicle (OMV) with the macrophage membrane vector (RV) to construct hybrid nanovesicle (ROMV) and encapsulated the bacterial metabolite trimethylamine N -oxide (TMAO), forming ROMV/TMAO. ROMV/TMAO mimicked the beneficial functions of intestinal probiotics by leveraging the immunomodulatory properties of OMV and TMAO, combined with the tumor-homing capabilities of RV. In human lung cancer organoids and multiple tumor models, selective tumor targeting and accumulation of ROMV/TMAO facilitated M1 polarization of tumor-associated macrophages and enhanced CD8 + T lymphocyte infiltration, ultimately inhibiting tumor growth. When combined with ROMV/TMAO, the immune checkpoint inhibitor α-PD-L1 exhibited superior antitumor efficacy than monotherapy. This study introduces a probiotic-inspired nanotherapeutic strategy for augmenting immune checkpoint therapy outcomes while addressing microbiome therapy safety challenges. probiotic-inspired nanomaterials for augmenting immune checkpoint therapy (ICT) outcomes while addressing microbiome therapy safety challenges. • A probiotic-inspired nanotherapeutic strategy for augmenting immune checkpoint therapy outcomes. • Tumor targeting of ROMV/TMAO facilitates M1 polarization of macrophages and enhances CD8 + T cells infiltration. • ROMV/TMAO significantly enhances Anti -PD-L1 therapy efficacy in human lung cancer organoids and multiple tumor models.