tLyP-1 peptide-modified MnO₂ co-delivering si-SLC16A1 and temozolomide synergistically suppresses glioblastoma via hypoxia modulation and metabolic stress.

Glioblastoma (GBM) is a highly lethal brain tumor with limited treatment efficacy due to therapy resistance and the blood-brain barrier (BBB). Here, we developed tLyP-1-modified polyethylene glycol (PEG)-coated hollow catalase-mimicking MnO₂-based nanocarriers (HM@si-SLC16A1/TMZ-tLyP-1, tLyP-NPs) for the targeted co-delivery of temozolomide (TMZ) and SLC16A1 siRNA (si-SLC16A1). These nanoparticles generate oxygen through H₂O₂ decomposition, alleviating tumor hypoxia and enhancing MRI imaging via Mn²⁺ release. In vitro, tLyP-NPs exhibited high siRNA loading efficiency, pH-responsive drug release, and effective SLC16A1 silencing, leading to reduced glioma cell viability and enhanced apoptosis under both normoxic and hypoxic conditions. tLyP-1 modification facilitated BBB penetration and glioma targeting, as evidenced by increased cellular uptake in a BMEC-C6 glioma co-culture model. In an orthotopic GBM rat model, the nanoparticles demonstrated superior tumor accumulation, prolonged T1-weighted MRI contrast, and enhanced therapeutic efficacy compared to non-modified formulations. Mechanistically, SLC16A1 silencing induced intracellular lactate accumulation, suppressed lactate-stimulated HCAR1/PI3K/AKT signaling, and promoted apoptosis in both in vitro and in vivo models. Histological analysis showed extensive tumor necrosis, increased apoptosis (Caspase-3, TUNEL), reduced proliferation (Ki67), and alleviated hypoxia (HIF-1α). Survival analysis revealed significantly prolonged survival without systemic toxicity. Collectively, tLyP-NPs represent a promising multifunctional nanoplatform that integrates BBB penetration, TME-responsive drug release, and synergistic chemo-gene therapy for GBM treatment.