FAP-Anchored Retinoic Acid Nanoparticles for Stromal Reprogramming and Enhanced Intratumoral Oxaliplatin Delivery in Fibrotic Colorectal Tumours

In colorectal Cancer (CRC), cancer-associated fibroblasts (CAFs) and the fibrotic stroma generate form a dense stromal barrier that restricts the intratumoural exposure and spatial distribution of oxaliplatin. To enable local stromal remodelling of this pathological stromal compartment, we selected fibroblast activation protein (FAP) as a stromal target and co-assembled two amphiphilic conjugates, oncoFAP and retinoic acid (RA), into an FAP-directed RA nanoformulation termed LRA^FAP. LRA^FAP exhibited a uniform size distribution (107.1 ± 5.8 nm), remained stable for at least 7 d at 37 °C in PBS or serum-containing PBS, and showed accelerated esterase-responsive release. In a TGF-β-induced CAF-like model, LRA^FAP markedly suppressed the expression of CAF activation-associated markers, reducing FAP and Acta2 mRNA levels by approximately 70% and 60%, respectively. In vivo, LRA^FAP showed enhanced accumulation in CAF-enriched tumours and an increase in intratumoural oxaliplatin levels of approximately 2.5-fold relative to oxaliplatin alone. LRA^FAP also reduced Collagen deposition and CAF activation markers, and enhanced the antitumour efficacy of oxaliplatin while maintaining good tolerability. Collectively, these findings indicate that LRA^FAP promotes local stromal remodelling and improves intratumoural oxaliplatin exposure, thereby enhancing the efficacy of oxaliplatin-based chemotherapy in CRC.

cancer-associated fibroblast; colorectal cancer; extracellular matrix; fibroblast activation protein; retinoic acid.