Unfolding and Degradation of Micellar Immunodrug Carriers Derived From End Group Modified Aliphatic Poly(Carbonate)s with Acid‐Responsive Ketal Side Groups

Small-molecule immunodrugs hold significant promise for immunotherapeutic applications including vaccination and cancer therapy. However, their clinical use is limited by severe side effects resulting from systemic distribution. To address this challenge, a biodegradable, acid-responsive nanocarrier system designed for controlled immunodrug delivery in vivo is presented. It is based on polymeric micelles that disassemble in response to acidic environments, enabling site-specific particle unfolding following endocytosis by antigen-presenting cells. Its core structure features a hydrolysable aliphatic poly(carbonate) backbone, promoting both biocompatibility and biodegradability. The high precision of the applied ring-opening polymerization allows for polymer end group functionalization, including the integration of fluorophores for Förster resonance energy transfer (FRET)-based monitoring of particle integrity and unfolding. The observations reveal a pH-dependent disassembly profile both in vitro and in vivo. Comparative studies with non-responsive poly(carbonate)s demonstrate the superior performance of the acid-responsive design in selectively disassembling under acidic conditions and enhancing polymer backbone degradation. Furthermore, covalent conjugation of a small molecule Toll-like receptor 7/8 agonist promotes its controlled delivery in vitro and in vivo, resulting in improved immune cell uptake and regulated cytokine production. The findings underscore the potential of this biodegradable, acid-responsive micellar nanocarrier system as precision delivery platform for safer and effective immunotherapeutics.