Combining photodynamic therapy and ATM inhibition using modified bovine serum albumin: A co-delivery nano platform for eliciting pyroptosis and apoptosis to fuel TNBC therapy.

Triple-negative breast cancer (TNBC) presents a formidable challenge due to its poorest prognosis and limited array of treatment options available. Photodynamic therapy (PDT) has emerged as a potent therapeutic modality to generate intratumoral toxic reactive oxygen species (ROS) in combating refractory triple-negative breast cancer (TNBC). However, its therapeutic efficacy is compromised due to insufficient tumor accumulation and therapeutic resistance. Herein, an "all-in-one" tumor-therapeutic nanomedicine named HA@IR780@KU55933@BSA (HIKB) which integrated photosensitizer IR780 with ATM kinase inhibitor KU55933 was designed to facilitate drug delivery and target specific pathways involved in tumor PDT treatment resistance. Co-delivery of IR780 and KU55933 exacerbated intracellular ROS production, mitochondrial dysfunction and DNA damage to form a potent anti-TNBC therapeutic cyclical feedback loop and then induced pyroptosis and apoptosis of TNBC cells by activating the Caspase3/GSDME signaling pathway and regulating apoptosis-related protein expression, respectively. In vivo evaluations in the TNBC orthotopic xenograft mouse model demonstrated that the designed HIKB NPs could accumulate in tumor tissues and exert synergistic therapeutic effects. Altogether, this study described a self-assembling strategy for constructing an all-in-one nanomedicine that effectively integrates multiple therapeutic modalities to provide a comprehensive and systemic approach to tumor suppression.