TriCON: A Carbon-Based Triple-Modal Nanoplatform for Pancreatic Cancer Therapy

Pancreatic cancer, recognized for its high malignancy and tumor immunosuppressive microenvironment, has been refractory to conventional therapeutic modalities, necessitating the exploration of novel treatment strategies. Among these, reprogramming of the tumor immunosuppressive microenvironment is a promising strategy to enhance the efficacy of tumor immunotherapy. The CRISPR/Cas9 system-based gene editing further offers a viable approach for precise regulation of endogenous gene expression associated with tumor immunosuppression. Current delivery vectors face a trilemma between biosafety profiles, expansion capacity, and targeting accuracy. To this end, we developed a triple-modality therapeutic platform, termed TriCON (Triple Convergent Oncology Nanotherapy), characterized by three core mechanistic attributes: spatiotemporal convergence, stimuli-responsive controllability, and tumor-microenvironment modulatory conductivity. This orchestrated combination of rationally designed gene editing (targeting poliovirus receptor), nano-encapsulated doxorubicin (DOX) chemotherapy, and checkpoint blockade immunotherapy demonstrated enhanced synergistic antitumor activity in pancreatic ductal adenocarcinoma (PDAC) models, achieving tumor regression through enhanced chemotherapy, immunogenic cell death induction, and natural killer (NK) cells activation. The platform achieved superior in vivo gene editing (14.2% PVR editing efficiency) via optimized endosomal escape and CRISPR system release. This triaxial approach establishes a programmable nanotherapeutic paradigm that synergizes gene editing precision with chemo-immunotherapy, offering a novel framework for PDAC treatment.