Abstract

Regulation of the tumor microenvironment (TME) represents a promising strategy to enhance immunotherapy for glioblastoma (GBM) immunotherapy. Lactate dehydrogenase A (LDHA) is an attractive metabolic target for TME modulation. We developed cRGD-decorated, GBM cell membrane biomimetically modified lipid nanoparticles to co-deliver the sonosensitizer Ce6 and LDHA siRNA (Ce6/LDHA siRNA cRGD-BLNPs). The cRGD-cell membrane can endow LNPs with dual-targeting effect (cell membrane for homotypic targeting, cRGD for active targeting). Under ultrasound irradiation, immunogenic cell death (ICD) could be induced to release tumor-associated antigens (TAAs) and damage-associated molecular patterns (DAMPs), thereby activating immune responses. Additionally, LDHA siRNA regulated lactic acid metabolism to reverse the immunosuppressive TME. This work provides a paradigm for lactic acid metabolism and ICD mediated GBM treatment, with potential clinical applicability for improving GBM immunotherapy.