Abstract

A variety of Poly (ADP-ribose) polymerase inhibitors (PARPi) have been approved for the clinical treatment of breast cancers. However, pre-clinical and clinical evidences indicate that PARPi only benefits patients with homologous recombination (HR)-deficient breast cancers. Besides, the abnormal mechanical microenvironment of breast cancers severely restricts drug transport to tumor cells. Leveraging efforts from nanomedicine , mesoporous polydopamine (mP) with excellent biocompatibility and large specific surface area was employed to deliver both Olaparib (Ola), an FDA approved PARPi, and Doxorubicin (Dox), a typical DNA-damaging drug. In this nano drug delivery system (NDDS), mP operates not only as a drug carrier but also as a photothermal generator. Mechanistically, we revealed that locally mild photothermal therapy (M-PTT, around 43 ℃) on tumors was capable of inhibiting the HR repair pathway via dramatically downregulating the expressions of key HR-related proteins MRE11, RAD51 and BRCA2 . Concomitantly, in vivo results indicated that M-PTT could effectively repress cancer associated fibroblasts (CAFs) by relieving hypoxia , resulting in diminution of dense extracellular matrix (ECM) of breast cancer (collagen Ⅰ and fibronectin decreased by 77.1% and 36.7%, respectively). Furthermore, the reduction of ECM normalized both tumor mechanics and tumor vasculature , facilitating drug delivery and penetration. Therefore, with the aid of M-PTT, this NDDS induces potent DNA damage, thereby enhancing antitumor efficacy (tumor inhibition rate of 86.1%) while minimizing systemic side effects. This work not only highlights the great potential of M-PTT-induced on-demand HR deficiency in clinical cancer therapy, but also reveals the potential mechanisms of M-PTT in inhibiting DNA damage repair and regulating tumor mechanics.