Regulation of CTLs/Tregs via Highly Stable and Ultrasound‐Responsive Cerasomal Nano‐Modulators for Enhanced Colorectal Cancer Immunotherapy

Abstract Immunotherapy is showing good potential for colorectal cancer therapy, however, low responsive rates and severe immune‐related drug side effects still hamper its therapeutic effectiveness. Herein, a highly stable cerasomal nano‐modulator (DMC@P‐Cs) with ultrasound (US)‐controlled drug delivery capability for selective sonodynamic‐immunotherapy is fabricated. DMC@P‐Cs’ lipid bilayer is self‐assembled from cerasome‐forming lipid (CFL), pyrophaeophorbid conjugated lipid (PL), and phospholipids containing unsaturated chemical bonds (DOPC), resulting in US‐responsive lipid shell. Demethylcantharidin (DMC) as an immunotherapy adjuvant is loaded in the hydrophilic core of DMC@P‐Cs. With US irradiation, reactive oxygen species (ROS) can be effectively generated from DMC@P‐Cs, which can not only kill tumor cells for inducing immunogenic cell death (ICD), but also oxidize unsaturated phospholipids‐DOPC to change the permeability of the lipid bilayers and facilitate controlled release of DMC, thus resulting in down‐regulation of regulatory T cells (Tregs) and amplification of anti‐tumor immune responses. After intravenous injection, DMC@P‐Cs can efficiently accumulate at the tumor site, and local US treatment resulted in 94.73% tumor inhibition rate. In addition, there is no detectable systemic toxicity. Therefore, this study provides a highly stable and US‐controllable smart delivery system to achieve synergistical sonodynamic‐immunotherapy for enhanced colorectal cancer therapy.