Bi-A@SR Nanoparticles Enable Tumor-Localized NO Release to Suppress HSP70 and Reverse Chemoresistance

Cervical cancer (CC) treatment is limited by chemoresistance, inadequate drug accumulation, and the lack of real-time monitoring. Among the underlying mechanisms, heat shock protein 70 (HSP70) mediates resistance to both chemotherapy and photothermal therapy, making it a rational target for intervention. To address these issues, we developed a novel type of cyclic RGD (cRGD) encapsulated SN38 and IR820 loaded bismuth selenide theranostic nanoplatforms-Bi₂Se₃-cRGD@SN38/IR820 nanoparticles (Bi-A@SR NPs) based on a bismuth selenide (Bi₂Se₃) as core decorated with cRGD for tumor targeting, and co-loaded with SN38 and IR820. The RGD peptide contains a guanidino group from its arginine residue that can serve as a donor for nitric oxide (NO) generation, enabling the construct to provide both tumor-homing capability and on-demand NO release. The nanoplatform integrates computed tomography (CT) imaging and NIR fluorescence imaging (NIRF) to verify delivery and guide therapy. Upon 808 nm irradiation, photothermal and photodynamic effects generate hyperthermia and reactive oxygen species (ROS), which trigger on-site NO production from the RGD arginine moiety. This NO suppresses therapy-induced HSP70 upregulation, counteracting stress adaptation and enhancing chemo-phototherapy efficacy. By combining imaging-guided delivery, on-demand NO sensitization, and HSP70 inhibition, this nanotheranostic strategy offers a coordinated approach to improving treatment outcomes in CC.