Mucin-capped CuS nanoparticles for mitochondrial targeted NIR-II photothermal therapy and photoacoustic imaging

Small molecules, known for their superior penetration abilities, are often preferred for deep-tissue cancer Photoacoustic Imaging (PAI) and Photothermal Therapy (PTT). However, they generally produce weaker photo- acoustic signals than nanoparticles, which offer stronger signals and enhanced targeting capabilities. Mucin, a natural biomolecule, has not been explored for synthesizing copper sulfide (CuS) nanoparticles. This study investigates using Mucin as a CuS (Mu@CuS) capping agent to enhance their stability for optical theranostic applications. The resulting nanoparticles were less than 10 nm in size, crystalline in nature, and exhibited absorbance in the NIR II region. Photothermal ability and photoacoustic contrast ability were established. To improve targeting and cellular uptake, Rhodamine B was conjugated to the mucin-coated CuS nanoparticles (Mu@CuS-Rh), exploiting the negative charges on cancer cell membranes to deliver the nanoparticles specifically to mitochondria. Experiments on 2D cell culture and 3D spheroid models demonstrated deep tumor penetration and effective photothermal therapeutic effects. In vivo, analysis of Mu@CuS-Rh nanoparticles showed significant tumor uptake and retention for up to 7 h, with notable accumulation in hypoxic tumor regions. These findings highlight the potential of Mu@CuS nanoparticles, which can be further explored for hypoxic tumor imaging and targeted therapy.