Cutting-edge, drug-free targeted cancer therapeutic: Smart folate-conjugated copolymer intrinsically disables the YAP/TAZ-HIPPO oncoproteins and abrogates pancreatic cancer progression and metastasis

Background: Pancreatic ductal adenocarcinoma (PDAC) is driven by intrinsic chemoresistance and adaptive survival pathways, including the Hippo/YAP axis and hypoxic signaling. Systemic cytotoxic therapy is limited by severe toxicity and poor tumor penetration. Recent advances suggest functionalized nanostructures can possess intrinsic biological activity beyond serving as inert carriers. We hypothesized that the precision of ultrasensitive nano-biosensing could be repurposed for therapeutic intervention and in vivo tracking. Methods: A 350 kDa folate-functionalized amphiphilic alternating copolymer (FA-DABA-SMA) was synthesized and tested as a "drug-free" nanotherapeutic in a RAG2×Cgamma double-mutant xenograft model of PANC-1 human pancreatic cancer. Mice received weekly intravenous FA-DABA-SMA monotherapy, compared to curcumin and untreated controls. Efficacy was assessed by tumor volume and metastatic burden. Mechanistic analysis used immunohistochemistry and immunofluorescence to evaluate Hippo pathway effectors (YAP, TAZ), proliferation (Ki67), and hypoxic signaling (HIF-1alpha, VEGF, CA9). Results: FA-DABA-SMA achieved 69% tumor reduction versus controls (p < 0.001), outperforming curcumin, and abrogated liver and lung metastases. Multivalent folate receptor engagement sequestered Hippo effectors (YAP/TAZ) in the cytoplasm, preventing nuclear translocation. Treatment collapsed hypoxic survival machinery and suppressed vasculogenic mimicry (CD31/CD34). Conclusions: FA-DABA-SMA is a novel intrinsic nanotherapeutic disabling PDAC survival pathways without cytotoxic cargo, supporting translation as a non-toxic clinical candidate for metastasis prevention.