A Novel Integrated Therapeutic Strategy for Pancreatic Ductal Adenocarcinoma Based on Synergistic siRNA and Intelligent Nanocarriers

Pancreatic Ductal Adenocarcinoma (PDAC) stands among the most aggressive forms of cancer. Its clinical treatment confronts two core difficulties. On one hand, over 90% of cases carry KRAS gene mutations. Yet the mutant KRAS protein lacks traditional binding pockets for drugs. This has long made it an undruggable target. On the other hand, PDAC tumors are wrapped in a dense, fibrotic stroma. This stroma acts as a tough barrier. It greatly limits how well therapies can enter and accumulate inside the tumor. Conventional treatments often fail against both challenges. Thus, their efficacy remains limited. The work builds on the pathological mechanisms of PDAC. Here, oncogenic KRAS signaling drives two processes: tumor cell growth and stromal remodeling. We propose a new integrated and synergistic treatment paradigm. This strategy brings together two core modules. First is a synergistic silencing module. It uses combinatorial siRNA to silence KRAS and key downstream signaling nodes at the mRNA level. This aims to overcome single‑target limits and signaling compensation that causes resistance. Second is an intelligent delivery platform. It involves a multifunctional, biodegradable nanocarrier. This carrier integrates surface engineering, active targeting, stimulus‑responsive release, and endosomal escape. In this way, it systematically overcomes biological barriers from circulation to cytoplasmic release. This allows precise, efficient siRNA delivery. This strategy's innovation lies in a shift in paradigm. It moves from passive, single‑target delivery to intelligent, synergistic delivery against multiple targets. It targets tumor cells and their supportive microenvironment together. Therefore, it provides a systemic solution. It holds clear potential for clinical translation in overcoming PDAC treatment resistance.