Pancreatic cancer is among the most aggressive malignancies, showing poor responses to conventional chemotherapy. Sonodynamic therapy (SDT) has emerged as a promising treatment. However, cancer-associated fibroblasts (CAFs) restrict SDT efficacy and contribute to poor therapeutic response. To overcome this barrier, we developed a CAF-targeted SDT–chemotherapy system to remodel the drug-resistant tumor microenvironment and enhance therapeutic outcomes. Using the GSE212966 dataset, Fibronectin (Fn) was identified as the therapeutic target in CAFs. We then constructed FnBPA5-IR-CF3@Dox, a nano micelle integrating CAF targeting, SDT, and doxorubicin (Dox) delivery. The system exhibited high drug loading capacity, good dispersion, stability, and selective accumulation in CAFs. In multicellular tumor spheroids and orthotopic pancreatic cancer mouse models, FnBPA5-IR-CF3@Dox + US treatment achieved significant antitumor efficacy by selectively eliminating CAFs, inhibiting stromal proliferation, reducing interstitial fluid pressure, enhancing intratumoral drug penetration. This CAF-targeted SDT-chemotherapy strategy markedly improved chemotherapy effectiveness and suppressed tumor growth. In conclusion, our study demonstrates that CAF-targeted SDT combined with chemotherapy provides an effective approach for reprogramming the tumor microenvironment and offers a promising therapeutic avenue for pancreatic cancer treatment. • CAF-targeted FnBPA5-IR-CF3@Dox integrates CAF targeting, SDT, and doxorubicin delivery. • FnBPA5-IR-CF3@Dox combined with US improves chemotherapy efficacy and suppresses tumor growth. • FnBPA5-IR-CF3@Dox combined with US selectively eliminates CAFs, inhibits stromal proliferation, lowers interstitial fluid pressure, and enhances intratumoral drug penetration.
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