Size matters: Altering antigen specific immune tolerance by tuning size of particles.

Precisely co-delivering antigens and immunosuppressants via nano/microcarriers to antigen-presenting cells (APCs) to induce antigen-specific immune tolerance represents a highly promising strategy for treating or preventing autoimmune diseases. The physicochemical properties of nano/microcarriers play a pivotal role in regulating immune function, with particle size and surface charge emerging as crucial parameters. In particular, very few studies have investigated micron-scale carriers of antigens. Herein, various nanoparticles and microparticles (NPs/MPs) with diverse particle sizes (ranging from 200 nm to 5 µm) and surface charges were prepared. Antigen peptides (MOG35-55) and immunosuppressants were encapsulated in these particles to induce antigen-specific immune tolerance. Two emulsifiers, PVA and PEMA, were employed to confer different surface charges to the NPs/MPs. The in vitro and in vivo studies demonstrated that NP/MP-PEMA could induce immune tolerance earlier than NP/MP-PVA and that NP/MP-PVA could induce immune tolerance more slowly and sustainably, indicating that highly negatively charged particles can induce immune tolerance more rapidly. Among the different sizes and charged particles tested, 200-nm-NP-PVA and 3-µm-MP-PEMA induced the greatest immune tolerance. In addition, the combination of NPs with MPs can further improve the induction of immune tolerance. In particular, combining 200 nm-NP-PVA with 3 µm-MP-PEMA or combining 500 nm-NP-PEMA with 3 µm-MP-PVA had optimal therapeutic efficacy. This study offers a new perspective for treating diseases by combining NPs with MPs and applying different emulsifiers to prepare NPs and MPs.

In vivo cisplatin-resistant neuroblastoma metastatic model reveals tumour necrosis factor receptor superfamily member 4 (TNFRSF4) as an independent prognostic factor of survival in neuroblastoma.

Neuroblastoma is the most common solid extracranial tumour in children. Despite major advances in available therapies, children with drug-resistant and/or recurrent neuroblastoma have a dismal outlook with 5-year survival rates of less than 20%. Therefore, tackling relapsed tumour biology by developing and characterising clinically relevant models is a priority in finding targetable vulnerability in neuroblastoma. Using matched cisplatin-sensitive KellyLuc and resistant KellyCis83Luc cell lines, we developed a cisplatin-resistant metastatic MYCN-amplified neuroblastoma model. The average number of metastases per mouse was significantly higher in the KellyCis83Luc group than in the KellyLuc group. The vast majority of sites were confirmed as having lymph node metastasis. Their stiffness characteristics of lymph node metastasis values were within the range reported for the patient samples. Targeted transcriptomic profiling of immuno-oncology genes identified tumour necrosis factor receptor superfamily member 4 (TNFRSF4) as a significantly dysregulated MYCN-independent gene. Importantly, differential TNFRSF4 expression was identified in tumour cells rather than lymphocytes. Low TNFRSF4 expression correlated with poor prognostic indicators in neuroblastoma, such as age at diagnosis, stage, and risk stratification and significantly associated with reduced probability of both event-free and overall survival in neuroblastoma. Therefore, TNFRSF4 Low expression is an independent prognostic factor of survival in neuroblastoma.