Mechanosensing-inspired targeted nanosystem rewires heterogenous cancer-associated fibroblasts via CHIP activation in pancreatic ductal adenocarcinoma

Heterogeneity of cancer-associated fibroblasts (CAFs) has emerged as a critical clinical challenge that undermines the efficacy of cancer therapies in desmoplastic tumours such as pancreatic ductal adenocarcinoma (PDAC). From a nanomedicine perspective, the ability to selectively modulate CAF populations, myofibroblastic CAF (myCAF) and inflammatory CAF (iCAF), remains a significant bottleneck in designing effective nanotherapeutic strategies. In this study, inspired by the mechanosensing nature of CAFs, we developed a peptide (AV3)-directed nanosystem to target ITGA5 receptor, a mechanoresponsive integrin that was found to be overexpressed in both myCAF and iCAF. AV3-conjugated nanoparticles (NPs) showed an efficient targeting to both CAF subtypes in vitro and in vivo after systemic administration, as confirmed by flow cytometry analyses. To functionally reprogram CAFs, we screened a library of small molecules and identified YL-109, an activator of CHIP E3 ubiquitin ligase via the aryl hydrocarbon receptor, as a potent dual modulator of myCAF and iCAF. Encapsulation of YL-109 with AV3-NPs enabled targeted re-programming of both CAF subsets in PDAC tumours in vivo , inhibiting desmoplasia, hypoxia and tumour-promoting signals. Co-treatment with CAF-targeted YL-109 NPs with gemcitabine – either alone or in combination of anti-PD-L1 – significantly enhanced the therapeutic efficacy and extended survival in PDAC-bearing mice. These effects were attributed to the induction of CHIP, reduction of collagen and enhanced infiltration of CD8 + T cells. This study contributes to the field of nanomedicine by introducing a rationally designed, dual-CAF-targeting nanosystem capable of overcoming stromal barriers in PDAC. This platform presents a new class of stroma-directed nanomedicines that integrate molecular targeting with microenvironment modulation to improve response to chemo- and immunotherapies.