MβCD@HA-Ad nanoparticles inhibit pancreatic cancer progression by targeting Caveolin-1/Piezo1/PLA2G4A-mediated lipid reprogramming.

Targeting lipid metabolism reprogramming presents a potential strategy to overcome drug resistance and enhance treatment outcomes in pancreatic cancer. Caveolin-1, a critical regulator of lipid metabolism, is highly expressed in pancreatic cancer, indicating its viability as a novel therapeutic target. To address the poor biocompatibility and inadequate tumor targeting associated with methyl-β-cyclodextrin (MβCD)-an indirect inhibitor of Caveolin-1 function through cholesterol chelation-novel MβCD@hyaluronic acid-adamantane (MβCD@HA-Ad) nanoparticles were developed to enhance therapeutic efficacy against pancreatic cancer. These nanoparticles achieve dual targeting via HA-mediated CD44 receptor binding and MβCD-driven Caveolin-1 metabolic inhibition, while exhibiting acid-responsive release properties that enhance their responsiveness to the pancreatic cancer microenvironment. In vitro studies suggest that MβCD@HA-Ad nanoparticles possess improved drug penetration capacity and enhanced antitumor effects. Inhibition of Caveolin-1 induces cell membrane stretching and increases Piezo1 sensitivity to mechanical stimuli, resulting in elevated intracellular Ca2+ influx, activation of PLA2G4A phosphorylation, and subsequent promotion of lipolysis. Concurrently, impaired endocytosis reduces fatty acid uptake, resulting in decreased lipid droplet accumulation. Non-targeted metabolomics analysis indicates that Caveolin-1 regulates glycerophospholipid and fatty acid metabolism in pancreatic cancer cells, influencing cellular growth, migration, and invasiveness. In a mouse model of pancreatic cancer, MβCD@HA-Ad nanoparticles exhibited excellent biosafety, efficient tumor-targeting capabilities, and sustained antitumor effects. By reducing lipid deposition in tumor tissues, these nanoparticles significantly delayed tumor progression and inhibited tumor cell proliferation. In summary, MβCD@HA-Ad nanoparticles exert precise antitumor effects by targeting Caveolin-1 and modulating the Piezo1/PLA2G4A signaling axis to disrupt lipid metabolism, thereby presenting a novel nanotherapeutic strategy for pancreatic cancer.