Metabolic Regulation of Biosynthesis of Melanin Nanoparticles for Enhancing Photothermal Therapy of Breast Tumor

Abstract Photothermal therapy (PTT) has received increasing attention for its minimally invasive and high spatiotemporal selectivity. However, most photothermal therapeutic agents are commonly produced through chemical or physical approaches, potentially introducing harmful factors to human health or the environment. Biosynthetic melanin nanoparticles exhibit excellent photothermal conversion efficiency and biocompatibility, making it a promising candidate for tumor PTT. In the previous study, it engineered Escherichia coli to express tyrosinase (tyr1) for the biosynthesis of melanin nanoparticles (Mel‐M). However, single‐enzyme overexpressing system is limited in yield and structure regulation.This study developed a multi‐enzyme system by overexpressing tyr1, tyrosinase‐related protein 1 (Tyrp1), and dopachrome tautomerase (Dct) through metabolic engineering strategy.The multi‐enzyme system successfully improving the yield of melanin nanoparticles (Mel‐A), with greater polymerization and stronger near‐infrared (NIR) absorption. The resulting Mel‐A not only possesses good photothermal stability and biocompatibility, but also displays higher photothermal conversion efficiency (66.5%) with good photoacoustic imaging (PAI) performance, significantly enhancing the efficacy of photothermal therapy of breast tumor. The study provides a promising strategy to regulate biosynthesis of melanin nanoparticles for improving their applications in cancer diagnosis and therapy.