The limited
tumor tissue penetration of many nanoparticles remains a formidable challenge to their therapeutic efficacy. Although several photonanomedicines have been applied to improve
tumor penetration, the first near-infrared window mediated by the low optical tissue penetration depth severely limits their anticancer effectiveness. To achieve deep optical tissue and
drug delivery penetration, a near-infrared second window (NIR-II)-excited and pH-responsive ultrasmall
drug delivery nanoplatform was fabricated based on BSA-stabilized
CuS nanoparticles (BSA@
CuS NPs). The BSA@
CuS NPs effectively encapsulated
doxorubicin (DOX) via strong electrostatic interactions to form multifunctional nanoparticles (BSA@
CuS@DOX NPs). The BSA@
CuS@DOX NPs had an ultrasmall size, which allowed them to achieve deeper
tumor penetration. They also displayed stronger NIR II absorbance-mediated deep optical tissue penetration than that of the NIR I window. Moreover, the multifunctional nanoplatform preferentially accumulated in
tumor sites, induced
tumor hyperthermia, and generated remarkably high ROS levels in
tumor sites upon NIR-II
laser (1064 nm) irradiation. More importantly, our strategy achieved excellent synergistic effects of
chemotherapy and
phototherapy (chemophototherapy) under the guidance of photothermal imaging. The developed nanoparticles also showed good biocompatibility and bioclearance properties. Therefore, our work demonstrated a facile strategy for fabricating a multifunctional nanoplatform that is a promising candidate for deep
tumor penetration as an effective antitumor
therapy.