Peptide nanovaccine conjugated via a retro-Diels-Alder reaction linker for overcoming the obstacle in lymph node penetration and eliciting robust cellular immunity.

Nanoparticles have been regarded as a promising vaccine adjuvant due to their innate immune potentiation and enhanced antigen transport. However, the inefficient infiltration into the lymph node (LN) paracortex of nanoparticles caused by subcapsular sinus (SCS) obstruction is the main challenge in further improvement of nanovaccine immune efficacy. Herein, we propose to overcome paracortex penetration by using nanovaccine to spontaneously and continuously release antigens after retention in the SCS. In detail, we utilized a spontaneous retro-Diels-Alder (r-D-A) reaction linker to connect poly{(2-methyl-2-oxazoline)80-co-[(2-butyl-2-oxazoline)15-r-(2-thioethyl-2-oxazoline)8]} (PMBOxSH) and peptides for the peptide nanovaccine construction. The r-D-A reaction linker can spontaneously break over time, allowing the nanovaccine to release free antigens and adjuvants upon reaching the LN, thereby facilitating the entry of released antigens and adjuvants into the interior of the LNs. We showed that the efficacy of the peptide nanovaccine constructed using this dynamic linker could be significantly improved, thus greatly enhancing the tumor inhibition efficacy in the B16-OVA model. This dynamic-covalent-chemistry-based vaccine strategy may inspire designing more efficient therapeutic vaccines, especially those that require eliciting high-amount T cell responses.

A polyamino acid-based phosphatidyl polymer library for in vivo mRNA delivery with spleen targeting ability.

A qualified delivery system is crucial for the successful application of messenger RNA (mRNA) technology. While lipid nanoparticles (LNPs) are currently the predominant platform for mRNA delivery, they encounter challenges such as high inflammation and difficulties in targeting non-liver tissues. Polymers offer a promising delivery solution, albeit with limitations including low transfection efficiency and potential high toxicity. Herein, we present a poly(L-glutamic acid)-based phosphatidyl polymeric carrier (PLG-PPs) for mRNA delivery that combines the dual advantages of phospholipids and polymers. The PLGs grafted with epoxy groups were firstly modified with different amines and then with alkylated dioxaphospholane oxides, which provided a library of PLG polymers grafted with various phosphatidyl groups. In vitro studies proved that PLG-PPs/mRNA polyplexes exhibited a significant increase in mRNA expression, peaking 14 716 times compared to their non-phosphatidyl parent polymer. Impressively, the subset PA8-PL3 not only facilitated efficient mRNA transfection but also selectively delivered mRNA to the spleen instead of the liver (resulting in 69.73% protein expression in the spleen) once intravenously administered. This type of phosphatidyl PLG polymer library provides a novel approach to the construction of mRNA delivery systems especially for spleen-targeted mRNA therapeutic delivery.

Monoamine oxidase B inhibits epithelial-mesenchymal transition and trigger apoptosis via targeting ERK1/2 signaling pathway in head and neck squamous cell carcinoma.

BACKGROUND: Monoamine oxidase B (MAOB), a flavin monoamine oxidase, regulates biogenic and xenobiotic amine oxidative deaminization. We demonstrate MAOB expression in head and neck epithelium and its biological importance in head and neck squamous cell carcinoma (HNSCC) development. METHODS: First, we found a possible MAOB downregulation in HNSCC using bioinformatic analysis. Second, we validated MAOB expression changes in vitro and assessed its tumorigenicity in HNSCC. Finally, preclinical xenograft models further confirmed our findings. RESULTS: Results proved that MAOB was significantly reduced in HNSCC tissues and cell lines. By comparing MAOB localization in patient specimens, we found that epithelial basal cells express MAOB and that it changes throughout HNSCC development. We observed that MAOB overexpression inhibited HNSCC cell malignancy via lentiviral transfection. We additionally discovered that selegiline partly counter-regulated MAOB overexpression-induced phenotypes in HNSCC cells. CONCLUSIONS: We found that MAOB is a potent biomarker and a unique and essential indication of HNSCC carcinogenesis.

Construction of hyperbranched polysiloxane-based multifunctional fluorescent prodrug for preferential cellular uptake and dual-responsive drug release.

Hyperbranched polymers hold great promise in nanomedicine for their controlled chemical structures, sizes, multiple terminal groups and enhanced stability than linear amphiphilic polymer assemblies. However, the rational design of hyperbranched polymer-based nanomedicine with low toxic materials, selective cellular uptake, controlled drug release, as well as real-time drug release tracking remains challenging. In this work, a hyperbranched multifunctional prodrug HBPSi-SS-HCPT is constructed basing on the nonconventional aggregation-induced emission (AIE) featured hyperbranched polysiloxanes (HBPSi). The HBPSi is a biocompatible AIE macromolecule devoid of conjugates, showing a high quantum yield of 17.88% and low cytotoxicity. By covalently grafting the anticancer drug, 10-hydroxycamptothecin (HCPT), to the HBPSi through 3,3'-dithiodipropionic acid, HBPSi-SS-HCPT is obtained. The HBPSis demonstrate obvious AIE features and it turned to aggregation-caused quenching (ACQ) after grafting HCPT owing to the FRET behavior between HBPSi and HCPT in HBPSi-SS-HCPT. In addition to on-demand HCPT release in response to changes in environmental pH and glutathione, a series of in vitro and in vivo studies revealed that HBPSi-SS-HCPT exhibits enhanced accumulation in tumor tissues through the enhanced permeation and retention (EPR) effect and preferential cancer cell uptake by charge reversal, thus resulting in apoptotic cell death subsequently. This newly developed multifunctional HBPSi-SS-HCPT prodrug provides a biocompatible strategy for controlled drug delivery, preferential cancer cell uptake, on-demand drug release and enhanced antitumor efficacy.

Interaction analysis between germline genetic variants and somatic mutations in head and neck cancer.

OBJECTIVES: To evaluate interactions between germline genetic variants and somatic mutations in head and neck cancer (HNC). METHODS: The region enrichment analysis was performed to evaluate the enrichment of cancer driver genes (CDGs) in susceptibility regions. The pathway enrichment analysis was performed to identify common pathways of cancer driver genes and susceptibility genes. The association analysis was performed to evaluate the relationships between germline variants and somatic mutations. Stratified analysis was performed based on HPV status. RESULTS: A total of 18 risk SNPs, 149 cancer susceptibility genes (CSGs), and 211 CDGs were included. Enrichment analysis revealed that CDGs were significantly enriched in susceptibility regions (P = 0.048) and CSGs were significantly enriched in CDGs (P = 0.006). The CSGs and CDGs were commonly enriched in seven pathways. The rs1229984 was associated with truncation mutation within five pathways (P = 0.0026). The rs1453414 was associated with somatic mutations in RBM15 (P = 0.0012). The rs310518 was significantly associated with signature 15, and rs259919 was significantly associated with signature 6. The HPV status significantly influenced the association between risk SNPs and somatic mutations, copy number values, and mutation signatures. CONCLUSION: These results provide novel insights for germline-somatic interactions in HNC, which will enhance the understanding of the molecular mechanisms of germline variants with somatic mutations in HNC.

Identification of enhancer RNAs for the prognosis of head and neck squamous cell carcinoma.

BACKGROUND: Enhancer RNAs (eRNAs) play an important role in carcinogenesis. The landscape of eRNAs in head and neck squamous cell carcinoma (HNSCC) remains largely unknown. METHODS: The eRNA expression matrix was obtained from the enhancer RNA in the cancer database. Functional enrichment analyses were performed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG). Prognostic eRNAs were identified using Cox regression analysis, and a prognostic prediction model was constructed based on coefficients. RESULTS: KEGG analysis showed that eRNA-related transcription factors were mainly enriched in herpes simplex virus 1 (HSV1) infection. The zinc finger (ZNF) family may play an essential role in HNSCC. ENSR00000188847, ENSR00000250663, ENSR00000313345, ENSR00000317887, and ENSR00000336429 were identified. The prediction model was robust. CONCLUSIONS: We constructed a robust 5-eRNA prognostic prediction model, and these eRNAs are potential biomarkers for HNSCC prognosis.