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

## TL;DR

TriCON is a new nanotherapy platform that combines gene editing, chemotherapy, and immunotherapy to treat pancreatic cancer more effectively.

## Contribution

TriCON introduces a triple-modality nanotherapeutic platform that synergizes CRISPR/Cas9 gene editing with chemotherapy and immunotherapy for PDAC treatment.

## Key findings

- TriCON achieved tumor regression in PDAC models through enhanced chemotherapy and immunogenic cell death.
- The platform demonstrated 14.2% PVR editing efficiency via optimized endosomal escape and CRISPR system release.
- TriCON activated natural killer cells and synergized gene editing precision with chemo-immunotherapy.

## Abstract

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.

We developed TriCON, a triple‐modality nanotherapeutic platform, to treat pancreatic ductal adenocarcinoma (PDAC) by synergizing gene editing, chemotherapy, and immunotherapy. TriCON utilizes CRISPR/Cas9 to target the poliovirus receptor (PVR), combined with nano‐encapsulated doxorubicin and checkpoint blockade. This approach achieved significant tumor regression in PDAC models through enhanced chemotherapy, immunogenic cell death, and NK cell activation, establishing a promising programmable nanotherapeutic paradigm.