A copper-based ascorbic acid-activatable gel for postoperative glioblastoma therapy

Glioblastoma (GBM) is prone to rapid postoperative recurrence, primarily due to its invasive growth pattern and immunosuppressive microenvironment. To combat these challenges, we developed an ascorbic acid (AA)-responsive implantable gel crosslinked by copper ions, denoted as CuTR-gel, for postoperative GBM therapy. CuTR-gel leveraged the copper-chelating properties of sodium alginate (SA) to co-deliver TPD-Cu (a novel ascorbic acid-activated copper complex prodrug) and R848 (a TLR7/8 agonist). Upon implantation, endogenous AA in GBM microenvironment triggered TPD-Cu cleavage to release strong chelator diethyldithiocarbamate (DTC). The liberated DTC then competed for the copper ions that served as cross-linking points within the gel, leading to the in situ formation of the copper complex Cu(DTC)₂. Simultaneously, copper dissociation from the gel network enabled controlled R848 release. The cytotoxic Cu(DTC)₂ complex exerted direct tumoricidal effects on residual cells while concurrently initiating immunogenic cell death (ICD) pathways that generate robust immune responses. The concomitant release of R848 further synergized with this process to amplify anti-tumor immunity. With the sustained drug release property, CuTR-gel offers immediate cytocidal effects coupled with durable immune activation for comprehensive postoperative management, demonstrating significant potential for long-term prevention of GBM recurrence.