Hyaluronic acid nanoparticles encapsulated microRNA-125b repolarizes tumor-associated macrophages in pancreatic cancer

Aim: To investigate a novel strategy to target tumor-associated macrophages and reprogram them to an antitumor phenotype in pancreatic adenocarcinoma (PDAC). Methods: M2 peptides were conjugated to HA-PEG/HA-PEI polymer to form self-assembled nanoparticles with miR-125b. The efficacy of HA-PEI/PEG-M2peptide nanoparticles in pancreatic tumors from LSL-KrasG12D/+, LSL-Trp53R172H/+, Pdx1-Cre genetically engineered mice was evaluated. Results: In vitro M2 macrophage-specific delivery of targeted nanoformulations was demonstrated. Intraperitoneal administration of M2-targeted nanoparticles showed preferential accumulation in the pancreas of KPC-PDAC mice and an above fourfold increase in the M1-to-M2 macrophage ratio compared with transfection with scrambled miR. Conclusion: M2-targeted HA-PEI/PEG nanoparticles with miR-125b can transfect tumor-associated macrophages in pancreatic tissues and may have implications for PDAC immunotherapy. Lay abstract In pancreatic ductal adenocarcinoma (PDAC) tumor-associated macrophages (TAM) play a major role in tumor progression. Reprogramming of TAMs from a predominant protumoral phenotype to antitumoral phenotype is a promising strategy for PDAC. CD44 targeting hyaluronic acid-poly(ethylenimine) (HA-PEI/PEG)-based nanoparticles encapsulating miR-125b and macrophage-specific delivery and accumulation in the tumor tissue of LSL-Kras(G12D/+), LSL-Trp53(R172H/+), Pdx1-Cre (KPC) genetically engineered mice were found. The pancreatic tumors show a switch of macrophage phenotype from protumoral to antitumoral.

Automated summary

The study demonstrated successful targeted delivery of M2 peptide-conjugated miR-125b with HA-PEI/PEG nanoparticles to tumor-associated macrophages in pancreatic tissues, leading to a potential antitumor effect in genetically engineered mice models of PDAC.