A sonosensitizing hydrogel with tumour-confined stability for intrinsically targeted sonodynamic therapy

Cancer sonodynamic therapy (SDT) has attracted increasing attention in recent years due to its superior spatiotemporal control over chemotherapy and deeper penetration than photodynamic therapy (PDT). However, ultrasound (US) is difficult to be precisely focused on tumours. Hence, sonosensitizers that diffuse into healthy tissues may be accidently excited to generate reactive oxygen species (ROS), resulting in off-target toxicity. More importantly, current sonosensitizers exhibit high toxicity and are not biodegraded after SDT, potentially leading to systemic toxicity. Here, we developed a chitosan-oxalate hydrogel (Chi-OA) that is only stable in tumour for tumour-confined SDT. Without the need to load any traditional sonosensitizers, the hydrogel relied on the intrinsically present oxalate ions to generate ROS under US irradiation. Following intratumoural injection, the hydrogel was stable and exhibited high ROS generation yield in tumour microenvironment (TME) under US irradiation. In contrast, it degraded in healthy tissues and exhibited a lower ROS yield. This enabled SDT to be confined within the tumour and allowed the hydrogel to degrade and be cleared after SDT.