Tumor microenvironment-activatable nanocatalysts with chemodynamic therapy and enhanced autophagy for specific treatment of oral squamous cell carcinoma

Abstract

Adjuvant therapy following surgery is imperative for enhancing the prognosis of patients with oral squamous cell carcinoma (OSCC) in the clinical setting. Nevertheless, challenges such as treatment resistance mediated by the tumor microenvironment (TME), systemic toxicity, and adverse side effects hinder the effectiveness of conventional adjuvant therapy. In this context, we introduce a novel nanocatalyst denoted as MnO_2-x@HA-CCM (MnHA@CCM NC) designed specifically for treating OSCC. This nanocatalyst exerts targeted anti-tumor effects through TME-activatable chemodynamic therapy (CDT) and tumoricidal autophagy. The MnHA@CCM NCs exploit the biocompatibility of hyaluronic acid (HA) coating and the homologous targeting effect of cancer cell membrane (CCM) camouflage, ensuring safe in vivo delivery and specific accumulation at tumor sites. Following intracellular uptake, Fenton-like Mn²⁺ is generated by consuming glutathione (GSH) within the TME. Subsequently, Mn²⁺ catalyzes the overproduced H₂O₂ to generate reactive oxygen species (ROS), inducing cell apoptosis through mitochondrial damage. Additionally, phagocytized NCs and the resultant ROS accumulation in tumor cells elevate the autophagy flux, leading to autophagosome overload and consequent tumoricidal autophagy. Notably, normal cells without TME-catalytic CDT undergo mild protective autophagy to rebalance the stimulation of NCs. As a result, the TME-activatable MnHA@CCM NCs demonstrate a therapeutic efficacy in inhibiting cancer cell growth both in vitro and in vivo. This study presents a targeted treatment strategy for OSCC tumors while sparing normal cells, offering a potential alternative in the realm of adjuvant therapy.

Keywords: Autophagy; Chemodynamic therapy; MnO(2−x)@HA-CCM nanocatalysts; Oral squamous cell carcinoma; Tumor microenvironment.