Inflammation-Responsive Polyion Complex Vesicles for Autoimmune Disease Therapy via Cell-Free DNA Scavenging and Inflammatory Microenvironment Modulation

Cell-free DNA (cfDNA) scavenging represents a promising anti-inflammatory modality for autoimmune disease (AID) treatment. However, it remains challenging for existing systems to achieve inflammation-targeted cfDNA scavenging and the management of cfDNA-unrelated inflammatory pathways. Herein, inflammation-responsive polyion complex vesicles (PICsomes) are developed, bridging inflammation-instructed cfDNA scavenging, and methotrexate (MTX) delivery for AID management. A positively charged, PEGylated polypeptide with guanidine side chains (PEG-PG) is developed, which self-assembles with a negatively charged, <i>cis</i>-aconitic anhydride-modified poly-_L-lysine (PC) to form the PICsomes and encapsulate MTX disodium salt. The neutrally charged PICsomes feature prolonged blood circulation after systemic administration, allowing for passive accumulation to the inflamed tissues. In the slightly acidic inflammatory microenvironment, PC transforms from negatively charged to positively charged, thereby disintegrating the PICsomes and liberating the PEG-PG and MTX. Consequently, PEG-PG-mediated cfDNA scavenging and MTX-mediated immunosuppression cooperate to inhibit inflammation and ameliorate the inflammatory microenvironment, promoting tissue repair in AID mouse models including collagen-induced arthritis and 2,4,6-trinitrobenzenesulfonic acid-induced colitis.