Molecular-level regulating intersystem crossing of polyphenols: Engineering high-efficiency phytochemical photosensitizer for MRSA elimination

Abstract

Natural polyphenols-mediated green photosterilization is promising but remains challenging in practical applications due to their unsatisfactory performance with insufficient intrinsic energy level and ROS generation. In this work, the molecular-level engineering strategy of natural polyphenols (quercetin, QC) by p-Methoxybezaldehyde (MB)-induced nucleophilic substitution is constructed for enhanced photodynamic MRSA therapy. Both the experimental and theoretical results disclose that the unprecedented H-aggregates of QC-MB supramolecular realized accelerated ISC with minimizing the energy level difference (ΔEst), achieving enhanced photodynamic performance with 2.2-fold enhancement on ¹O₂ quantum yield (75 %) compared to free quercetin (33 %). The well-designed photosensitizer realizes efficient MRSA elimination: with enhanced killing efficacy from 30.44 % to 99.95 % in vitro and effective eradication of mature biofilms. Mechanism study and gene transcription analysis reveal that the combined therapy of optical stimuli with QC-MB achieves the dual mechanism of ROS attack and virulence regulation against MRSA infection during the whole infection process. Moreover, the excellent biocompatibility and anti-infectious in vivo demonstrate the engineered QC-MB as a promising strategy for MRSA therapy.