Functionalized neutrophil nanovesicles for targeted photodynamic immunotherapy and potentiation of checkpoint blockade in colorectal cancer 

ABSTRACT

Colorectal cancer (CRC) patients with microsatellite-stable tumors typically resist immune checkpoint blockade (ICB) due to an immunosuppressive “cold” microenvironment. Photodynamic therapy (PDT) generates reactive oxygen species (ROS) to ablate tumor cells and induce immunogenic cell death (ICD), potentiating antitumor immunity. We previously demonstrated that neutrophil-derived nanovesicles (NNVs) retain tumor-suppressive cytotoxic payloads, including granzymes and perforin. Here, we engineered RGD-functionalized neutrophil nanovesicles encapsulating Ce6-loaded liposomes (RNC) via co-extrusion for targeted CRC photoimmunotherapy. RGD functionalization drives specific binding to integrin αvβ3-overexpressing CRC cells and selective in vivo tumor accumulation. Upon 660 nm irradiation, robust RNC-generated ROS synergizes with NNV cytotoxic proteins to trigger potent apoptosis and pronounced ICD. The resulting damage-associated molecular patterns (DAMPs) stimulate dendritic cell maturation and prime tumor-specific CD4⁺ and CD8⁺ T cell responses, effectively remodeling the microenvironment. In tumor-bearing mice, systemic RNC administration combined with local irradiation suppressed primary subcutaneous tumor growth and elicited significant abscopal effects on distant, non-irradiated tumors. Notably, co-administration with PD-1 blockade further amplified antitumor efficacy and systemic immune activation. This biomimetic nanoplatform integrates active targeting, photodynamic cytotoxicity, and ICD-driven immune priming, offering a synergistic strategy to convert “cold” CRC tumors into “hot” lesions and enhance checkpoint inhibitor therapy.

PMID:42714955 | DOI:10.1039/d6nr01109h