Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor and treatment is very challenging. Despite the recent advances in drug delivery systems, various approaches that allow sufficient deposition of anti-cancer drugs within the brain remain unsuccessful due to limited drug delivery throughout the brain. In this study, we utilized an intranasal (IN) approach to allow delivery of anti-cancer drug, encapsulated in PLGA nanoparticles. PLGA nanoparticles were modified with the RGD ligand to enable A_vβ₃ expressing tumor-specific delivery. IN delivery of RGD-conjugated-doxorubicin (DOX)-loaded-PLGA-nanoparticles (RGD-DOX-NP) showed cancer-specific delivery of NP and inhibition of brain tumor growth compared to the free-DOX or non-modified DOX-NP in the C6-implantated GBM model. Further, IN treatment with RGD-DOX-NP induces apoptosis in the tumor region without affecting normal brain cells. Our study provides therapeutic evidence to treat GBM using a non-invasive IN approach, which may further be translated to other brain-associated diseases.

Adipose tissue macrophage (ATM)-mediated inflammation is a key feature contributing to the adverse metabolic outcomes of dietary obesity. Recruitment of macrophages to obese adipose tissues (AT) can occur through the engagement of CCR2, the receptor for MCP-1 (monocyte chemoattractant protein-1), which is expressed on peripheral monocytes/macrophages. Here, we show that i.p. administration of a rabies virus glycoprotein-derived acetylcholine receptor-binding peptide effectively delivers complexed siRNA into peritoneal macrophages and ATMs in a mouse model of high-fat diet-induced obesity. Treatment with siRNA against CCR2 inhibited macrophage infiltration and accumulation in AT and, therefore, proinflammatory cytokines produced by macrophages. Consequently, the treatment significantly improved glucose tolerance and insulin sensitivity profiles, and also alleviated the associated symptoms of hepatic steatosis and reduced hepatic triglyceride production. These results demonstrate that disruption of macrophage chemotaxis to the AT through cell-targeted gene knockdown strategies can provide a therapeutic intervention for obesity-related metabolic diseases. The study also highlights a siRNA delivery approach for targeting specific monocyte subsets that contribute to obesity-associated inflammation without affecting the function of other tissue-resident macrophages that are essential for host homeostasis and survival.

Targeted protein degradation (TPD) provides unique advantages over gene knockdown in that it can induce selective degradation of disease-associated proteins attributed to pathological mutations or aberrant post-translational modifications (PTMs). Herein, we report a protein degrader, PRZ-18002, that selectively binds to an active form of p38 MAPK. PRZ-18002 induces degradation of phosphorylated p38 MAPK (p-p38) and a phosphomimetic mutant of p38 MAPK in a proteasome-dependent manner. Given that the activation of p38 MAPK plays pivotal roles in the pathophysiology of Alzheimer's disease (AD), selective degradation of p-p38 may provide an attractive therapeutic option for the treatment of AD. In the 5xFAD transgenic mice model of AD, intranasal treatment of PRZ-18002 reduces p-p38 levels and alleviates microglia activation and amyloid beta (Aβ) deposition, leading to subsequent improvement of spatial learning and memory. Collectively, our findings suggest that PRZ-18002 ameliorates AD pathophysiology via selective degradation of p-p38, highlighting a novel therapeutic TPD modality that targets a specific PTM to induce selective degradation of neurodegenerative disease-associated protein.