DNA Repair Enzyme Regulation Strategy for Enhanced Pancreatic Neuroendocrine Tumor Therapy via Targeting siRNA-Lipid Nanoparticles.

Pancreatic neuroendocrine tumors (panNETs) originate from neuroendocrine cells with high rates of metastasis, rendering many patients ineligible for surgical resection. The first-line chemotherapeutic agent Temozolomide (TMZ) for metastatic panNETs faces challenges related to resistance, primarily mediated by the DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT). This resistance limits the long-term efficacy of TMZ in many patients. To overcome these challenges, we developed the lipid nanoparticles (LNPs) modified with somatostatin receptors (SSTRs) targeting peptide of Octreotide to codeliver the TMZ and MGMT-siRNA (LOTR) to improve the therapeutic efficacy of TMZ via inhibiting MGMT-mediated resistance and also reducing systemic toxicity caused by TMZ. The in vitro and in vivo results demonstrated that the LOTR system significantly sensitized the tumor response to TMZ, lowered drug resistance, and reduced off-target effects, offering a promising approach for the treatment of advanced panNETs.