A Self-Propelling Natural Polysaccharide Hydrogel for ROS-Triggered and Feedback-Enhanced Temozolomide Delivery against Glioblastoma

Temozolomide (TMZ) is the first-line chemotherapeutic agent for the most aggressive and lethal form of brain cancer, glioblastoma (GBM). However, the poor aqueous solubility, short plasma half-life, and dose-dependent hematotoxicity severely limited its clinical efficacy. While localized drug delivery systems offer a promising strategy to enhance therapeutic outcomes, their success hinges on precise responsiveness to dynamic tumor microenvironmental cues. In this study, a reactive oxygen species (ROS)-responsive, natural polysaccharide-based hydrogel (TMZ@TCNC/SA) was developed by using nanocellulose and alginate to enable stimuli-triggered delivery of TMZ for localized glioblastoma therapy. By incorporating ROS triggers on the polysaccharide structure, TMZ can be released from the hydrogel in response to a highly oxidative tumor microenvironment. Moreover, released TMZ could induce ROS generation and positively accelerate the TMZ release process, thereby achieving rapid drug accumulation at the tumor site. The hydrogel exhibited H2O2-triggered degradation (96% within 24 h), achieved exceptional TMZ loading (88%) with tumor-specific release (91%, pH 5.5), and reduced viability by 87% and suppressed the invasion by 79% in GBM cells. In vivo experiments demonstrated that the TMZ@TCNC/SA hydrogel had significantly reduced GBM recurrence. These findings suggest that the self-propelling TMZ@TCNC/SA hydrogel is a promising ROS-triggered drug delivery system for efficient GBM inhibition.