A plant vesicle-dendritic cell chimera for enhancing cancer immunotherapy

Abstract

Abstract The tumour microenvironment (TME) causes mitochondrial dysfunction in resident dendritic cells (DCs), resulting in inadequate antigen presentation and weak T cell priming. Herein, we identify hypoxia as a key factor for causing pathological mitochondrial fission in tumour-associated DCs, and develop a plant vesicle-DC chimera to relieve hypoxia-induced mitochondrial dysfunction for enhancing cancer immunotherapy. The biohybrid chimera is fabricated by loading algae-derived nanovesicles (ANVs) with genetically engineered CCR2 overexpressing-DCs. The CCR2-DC-ANVs target tumour by leveraging the C-C motif chemokine ligand 2 (CCL2) in tumours. Upon light exposure, the ANVs produce oxygen and NADPH to resolve hypoxic and oxidative stress, which reverse pathological mitochondrial fission in DCs. Mitochondrial network restoration alleviates endoplasmic reticulum stress, reduces lipid droplet accumulation, and initiates metabolic reprogramming to enhance antigen presentation and T cell priming of CCR2-DC-ANVs in the TME. The biohybrid chimera enhances therapeutic efficiency in humanized mouse models of breast cancer in female mice without requiring external tumour antigens. This approach highlights a cross-species chimera for next-generation DC therapy, and provides the basis for a nanobiotechnology platform to facilitate organelle medicine by combining photosynthesis with immunotherapy.