Biomimetic MXene Nanoplatform for Tumor-Specific Synergistic Phototherapy and Immune Reprogramming in Pancreatic Cancer

Abstract

Pancreatic cancer remains highly refractory to conventional therapies owing to its immunosuppression of the tumor microenvironment (TME) and dense stromal structure. Nanomaterial-based strategies offer promising avenues for integrating multimodal treatment and modulating immunosuppressive TME. Here, we utilize MXene nanosheets as the photothermal substrate, loading chlorophyll e6 (Ce6) as the photosensitizer, and coating with a hybrid membrane that is derived from cancer cells and thylakoid vesicles, which can achieve dual-mode photothermal and photodynamic therapy (PTT/PDT) under near-infrared light irradiation. Notably, the thylakoid membrane component facilitates in situ oxygen generation, effectively alleviates the hypoxia of the tumor, and significantly boosts reactive oxygen species (ROS) production for enhanced PDT. In vitro and in vivo research exhibit potent tumor suppression, exhibiting a 90% inhibition rate, achieved via synergistic hyperthermia and oxidative stress, accompanied by significant immunogenic cell death (ICD), dendritic cell (DC) maturation, and cytotoxic T-cell infiltration. Moreover, the combination of this nanoplatform with αPD-1 therapy can not only inhibit primary pancreatic tumor progression but also elicit abscopal effects and systemic antitumor immunity. This multifunctional nanoplatform presents a highly promising nanomedicine strategy for overcoming pancreatic cancer's therapeutic challenges by synergistically integrating phototherapy and immunotherapy, with clinical translational potential.