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

Abstract

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).

The biological function of Serpinb9 and Serpinb9-based therapy

“…These nanoparticles are particularly beneficial in targeting cancer cells while minimizing damage to healthy tissues (144)(145)(146)(147). This selective targeting reduces potential side effects and toxicity, thereby improving both the bioavailability and antitumor efficacy (148,149). One of the key advantages of nanoparticle-based drug delivery is the ability to engineer systems that release multiple drugs simultaneously into tumors, at a controlled rate or in response to specific triggers like pH, glutathione or reactive oxygen species (150).…”