In Situ Formation of Fibronectin-Enriched Protein Corona on Epigenetic Nanocarrier for Enhanced Synthetic Lethal Therapy

PARP inhibitors (PARPi)-based synthetic lethal therapy demonstrates limited efficacy for most cancer types that are homologous recombination (HR) proficient. To potentiate the PARPi application, a nanocarrier based on 5-azacytidine (AZA)-conjugated polymer (PAZA) for the codelivery of AZA and a PARP inhibitor, BMN673 (BMN) is developed. AZA conjugation significantly decreased the nanoparticle (NP) size and increased BMN loading. Molecular dynamics simulation and experimental validations shed mechanistic insights into the self-assembly of effective NPs. The small PAZA NPs demonstrated higher efficiency of tumor targeting and penetration than larger NPs, which is mediated by a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration of PAZA NPs. Furthermore, it is found that PAZA carrier sensitize the HR-proficient nonsmall cell lung cancer (NSCLC) to BMN, a combination therapy that is more effective at a lower AZA/BMN dosage. To investigate the underlying mechanism, the tumor immune microenvironment and various gene expressions by RNAseq are explored. Moreover, the BMN/PAZA combination increased the immunogenicity and synergized with PD-1 antibody in improving the overall therapeutic effect in an orthotopic model of lung cancer (LLC). An ultrasmall nanocarrier for the co-delivery of azacytidine (AZA) and BMN673 is developed. The nanocarrier is capable of recruiting fibronectin (FN) enriched protein corona, resulting in effective tumor targeting and penetration through FN/ITGA5 mediated transcytosis. Co-delivery of AZA and BMN673 to tumors enhances the synthetic lethal therapy and elicits antitumor immune response through the epigenetic modulation of AZA. The figure is created with BioRender.com. image