A redox-sensitive core-crosslinked nanosystem combined with ultrasound for enhanced deep penetration of nanodiamonds into tumors

Nanodiamonds (NDs) as drug delivery vehicles are of great significance in anticancer therapy through enhancing drug retention. However, the major barrier to clinical application of NDs is insufficient tumor penetration owing to their strong aggregation and low passive penetration efficiency. Herein, the core-crosslinked pullulan carrier, assembled using the visible light-induced diselenide (Se–Se) bond crosslinking method for encapsulating nanodiamonds-doxorubicin (NDX), is proposed to improve monodispersity. Furthermore, the core-crosslinked diselenide bond provides the nanosystem with redox-responsive capability and improved structural stability in a physiological environment, which prevents premature drug leakage and achieves tumor site-specific controlled release. What's more, ultrasound (US) is utilized to promote nanosystem intratumoral penetration via enlarged tumor vascular endothelium cell gaps. As expected, the nanosystem combined with ultrasound can enhance anti-tumor efficacy with deep penetration and excellent retention performance in a HepG2 xenograft mouse model. This study highlights the ability of the integrated therapeutic paradigm to overcome the limitation of nanodiamonds and the potential for further application in cancer therapy.