Precisely Engineered Block Copolymers for Efficient PTEN mRNA Therapy of Non-Small Cell Lung Cancer.

Restoring the tumor suppressor PTEN (phosphatase and tensin homolog) offers a promising therapeutic strategy for nonsmall cell lung cancer (NSCLC). In particular, mRNA-based therapy provides a compelling alternative to small molecules and DNA-based gene therapy, combining high specificity with an excellent safety profile. However, its clinical translation hinges on the development of safe and efficient delivery systems. In this study, we present a rationally designed diblock copolymer that mediates highly effective PTEN mRNA delivery both in vitro and in vivo. The copolymer consists of a stealth PEG block and a cationic binding block, with precisely engineered 3-acrylamidophenylboronic acid (AAPBA) and N-(3-dimethylaminopropyl) methacrylamide (DMAPMA) units. Following optimization of the PEG chain length, the structure PEG45-b-P(AAPBA21-co-DMAPMA18) achieved a critical balance of delivery properties, leading to enhanced cellular uptake, facilitated endosomal escape, and enabled mRNA release for protein translation. When further functionalized with folic acid (FA), the copolymer successfully restored PTEN expression and inhibited tumor growth (81.0% relative to the PBS control group) in vivo, with no significant toxicity observed under the tested conditions. We anticipate that this block copolymer-based PTEN mRNA delivery platform could provide a promising new approach for the treatment of NSCLC.