Mild photothermal therapy boosts nanomedicine antitumor efficacy by disrupting DNA damage repair pathways and modulating tumor mechanics

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.