In Vivo Synthesis of Metabolically Degradable π‑Conjugated Conductive Polymers Enabling Seamless Neural Interface Integration and Tissue Repair

Abstract The seamless integration of bioelectronics with neural tissues is essential for regulating biological signal transmission and understanding complex physiological functions. However, conventional bioelectronic materials face significant limitations, including poor interfacial integration at the cellular level and a lack of controlled degradation, which hinders effective signal transduction and long‐term biocompatibility. To address these challenges, a metabolically degradable π‐conjugated conductive polymer, poly(pyrrole‐3‐carboxylic acid) (PPyCA) is developed and synthesized enzymatically under physiological conditions. The electron withdrawing group, carboxylic acids, reduced the electron cloud density of the pyrrole ring, enhancing the pyrrole ring affinity toward superoxide anion and thereby promoting controlled degradation. The resulting hydrophilic PPyCA has strong tissue affinity, forms seamless bioelectronic interfaces, and undergoes complete metabolic degradation within months. In vivo studies have demonstrated that enzymatically synthesized PPyCA microvesicles (MVs) not only facilitate neural signal transmission but also promote nerve regeneration following injury. Mechanistic investigations revealed that PPyCA upregulates c‐FOS and related gene expression through the MAPK pathway, further supporting its role in nerve repair. Importantly, proteomic and metabonomic analyses confirmed the absence of cytotoxic effects. This study establishes a new paradigm for metabolizable electroactive polymers that enable seamless bioelectronic communication and programmed degradation, offering significant potential for biomedical applications.