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 H 2 O 2 -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.