Brain-targeting biomimetic nanoparticles for codelivery of celastrol and LY2157299 for reversing glioma immunosuppression

The treatment of glioblastoma remains a huge challenge due to the lack of an efficient way to deliver drugs across the blood-brain barrier (BBB), and the pharmacotherapy options are very limited. In this work, a biomimetic BBB-penetrating albumin nanosystem modified by a brain-targeting peptide was designed for co-delivering a TGF-beta receptor I (TGF beta RI) inhibitor (LY2157299) and an mTOR inhibitor (celastrol). The albumin nanosystem can target nAChRs overexpressed both on the BBB and glioma cells, thereby promoting drug delivery into the glioma. The biomimetic nanoparticles could repolarize tumor-associated macrophages (TAMs) from M2 to M1 phenotype by suppressing the STAT6 pathway, thereby reducing TGF-beta 1 secretion and inducing cell apoptosis. In addition, the treatment also blocked TGF-beta/SMAD2 signaling pathway. The glioma-targeting ability and thera-peutic efficacy were confirmed in an orthotopic glioma mouse model. The biomimetic nanoparticles significantly prolonged the survival rate, showing a decrease in the proportion of M2-like TAMs and the levels of TGF-beta 1 and lactic acid in the glioma tissues. This delivery and treatment strategy provides a new approach for the treatment of gliomas.

Automated summary

In this study, a biomimetic albumin nanosystem modified with a brain-targeting peptide was designed for efficient drug delivery to glioblastoma. The nanosystem demonstrated glioma-targeting ability and therapeutic efficacy by repolarizing tumor-associated macrophages and blocking the TGF-beta/SMAD2 signaling pathway. This delivery and treatment strategy provides a new approach for glioma treatment.