ROS-Responsive Cationic Polymers with Intrinsic Anti-InflammatoryActivity for Intracellular Protein Delivery

The intracellular delivery of protein drugs via nanocarriers offers significant potential for expanding their therapeutic applications. However, the unintended activation of innate immune responses and inflammation triggered by the carriers presents a major challenge, often compromising therapeutic efficacy. Here, we present oligoethylenimine-thioketal (OEI-TK), a reactive oxygen species-responsive cationic polymer with intrinsic anti-inflammatory properties, to overcome this challenge. OEI-TK self-assembles electrostatically with bovine serum albumin (BSA) to form stable nanoparticles (OTB NPs) with excellent encapsulation efficiency. In vitro studies confirmed that OTB NPs retained OEI-TK’s antioxidant and anti-inflammatory properties, enhanced biocompatibility, and efficiently delivered BSA into cells. Furthermore, OEI-TK facilitated the intracellular delivery of β-galactosidase while preserving its enzymatic activity, demonstrating its potential for functional protein transport. These findings highlight OEI-TK as a promising platform with dual benefits of inflammation modulation and intracellular protein delivery, holding potential for the synergistic treatment of inflammation-related diseases.