Photoactivatable Metal-Free Nanoplatform for Synergistic Carbon Monoxide and Photodynamic Antibacterial Therapy

The rising prevalence of multidrug-resistant (MDR) bacterial infections highlights the urgent need for innovative antimicrobial therapies that are both effective and industrially scalable. We report a metal-free, facilely prepared, and biocompatible nanoplatform (TCPP-HF@Lec) designed for synergistic antibacterial treatment via light-triggered codelivery of singlet oxygen (¹O₂) and carbon monoxide (CO). This system coencapsulates the photosensitizer tetrakis(4-carboxyphenyl)porphyrin (TCPP) and the CO-releasing prodrug 3-hydroxyflavone (3-HF) within a lecithin-based nanoparticle, enabling straightforward preparation with potential for large-scale pharmaceutical production. Upon 660 nm irradiation, TCPP generates ¹O₂, which not only induces photodynamic cytotoxicity but also activates 3-HF via oxidative decarbonylation, achieving spatiotemporally controlled CO release. Comprehensive physicochemical characterization revealed uniform morphology, excellent colloidal stability, and efficient dual-agent loading. <i>In vitro</i>, TCPP-HF@Lec exhibited potent, concentration-dependent antibacterial activity against Gram-positive strains, including <i>Staphylococcus aureus</i> TISTR1466, <i>Bacillus subtilis</i> TISTR008, and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA), achieving near-complete eradication under light irradiation. In contrast, Gram-negative bacteria (<i>Escherichia coli</i> TISTR780 and <i>Pseudomonas aeruginosa</i> TISTR781) showed negligible susceptibility, consistent with fluorescence imaging that revealed preferential nanoparticle uptake by Gram-positive bacteria lacking an outer membrane. By combining precise light-controlled activation with a production-friendly design, this dual-modality nanoplatform overcomes major limitations of conventional photodynamic therapy and CO-releasing molecules. TCPP-HF@Lec offers a promising approach for the scalable development of next-generation targeting antibacterial nanotherapeutics against MDR bacterial infections.