Sulfonium-Stapled Peptides-Based Neoantigen Delivery System for Personalized Tumor Immunotherapy and Prevention.

Neoantigen peptides hold great potential as vaccine candidates for tumor immunotherapy. However, due to the limitation of antigen cellular uptake and cross-presentation, the progress with neoantigen peptide-based vaccines has obviously lagged in clinical trials. Here, a stapling peptide-based nano-vaccine is developed, comprising a self-assembly nanoparticle driven by the nucleic acid adjuvant-antigen conjugate. This nano-vaccine stimulates a strong tumor-specific T cell response by activating antigen presentation and toll-like receptor signaling pathways. By markedly improving the efficiency of antigen/adjuvant co-delivery to the draining lymph nodes, the nano-vaccine leads to 100% tumor prevention for up to 11 months and without tumor recurrence, heralding the generation of long-term anti-tumor memory. Moreover, the injection of nano-vaccine with signal neoantigen eliminates the established MC-38 tumor (a cell line of murine carcinoma of the colon without exogenous OVA protein expression) in 40% of the mice by inducing potent cytotoxic T lymphocyte infiltration in the tumor microenvironment without substantial systemic toxicity. These findings represent that stapling peptide-based nano-vaccine may serve as a facile, general, and safe strategy to stimulate a strong anti-tumor immune response for the neoantigen peptide-based personalized tumor immunotherapy.

Intracellular Delivery of Stabilized Peptide Blocking MTDH-SND1 Interaction for Breast Cancer Suppression.

Triple-negative breast cancer is one of the most prevalent malignant cancers worldwide. Disrupting the MTDH-SND1 protein-protein interaction has recently been shown to be a promising strategy for breast cancer therapy. In this work, a novel potent stabilized peptide with a stronger binding affinity was obtained through rational structure-based optimization. Furthermore, a sulfonium-based peptide delivery system was established to improve the cell penetration and antitumor effects of stabilized peptides in metastatic breast cancer. Our study further broadens the in vivo applications of the stabilized peptides for blocking MTDH-SND1 interaction and provides promising opportunities for breast cancer therapy.

Multi-Body Biomarker Entrapment System: An All-Encompassing Tool for Ultrasensitive Disease Diagnosis and Epidemic Screening.

Ultrasensitive identification of biomarkers in biofluids is essential for the precise diagnosis of diseases. For the gold standard approaches, polymerase chain reaction and enzyme-linked immunosorbent assay, cumbersome operational steps hinder their point-of-care applications. Here, a bionic biomarker entrapment system (BioES) is implemented, which employs a multi-body Y-shaped tetrahedral DNA probe immobilized on carbon nanotube transistors. Clinical identification of endometriosis is successfully realized by detecting an estrogen receptor, ERß, from the lesion tissue of endometriosis patients and establishing a standard diagnosis procedure. The multi-body Y-shaped BioES achieves a theoretical limit of detection (LoD) of 6.74 aM and a limit of quantification of 141 aM in a complex protein milieu. Furthermore, the BioES is optimized into a multi-site recognition module for enhanced binding efficiency, realizing the first identification of monkeypox virus antigen A35R and unamplified detection of circulating tumor DNA of breast cancer in serum. The rigid and compact probe framework with synergy effect enables the BioES to target A35R and DNA with a LoD down to 991 and 0.21 aM, respectively. Owing to its versatility for proteins and nucleic acids as well as ease of manipulation and ultra-sensitivity, the BioES can be leveraged as an all-encompassing tool for population-wide screening of epidemics and clinical disease diagnosis.

Sulfonium-Driven Neoantigen-Released DNA Nanodevice as a Precise Vaccine for Tumor Immunotherapy and Prevention.

Peptide-based neoantigen vaccines hold tremendous potential for personalized tumor immunotherapy. However, effective delivery and controllable release of antigen peptides remain major challenges in stimulating robust and sustained immune responses. Programmable DNA nanodevices provide accurate fixed positions for antigens, which are convenient for the calculation of clinical dosage, and hold great potential as precise carriers. Here, a peptide-nucleic acid conjugate was prepared, which was driven by a propargyl sulfonium-based efficient and reversible bio-orthogonal reaction under weakly alkaline conditions, and folded into regular DNA nanodevice vaccines. The well-defined nanoplatform not only exhibits outstanding stability in serum, satisfactory safety, and effective internalization by antigen-presenting cells (RAW264.7 and BMDCs) but also obviously enhances cytokine (TNF-α, IL-6, and IL-12) secretion for further immune response. In vivo, the nanovaccine cooperating with OVA model antigens and CpG adjuvants stimulated an antigen-specific CD8+T cell response, significantly preventing the lung metastases of melanoma. In the B16-OVA tumor-bearing model, the growth inhibition rate of melanoma reached up to 50%. Similarly, the DNA nanodevice with neoantigen induced up to a maximum degree of complete MC-38 tumor regression in 80% of mice, possibly owing to antigen peptide reversible release driven by sulfonium and further cross-presentation. In brief, this study demonstrates that DNA nanodevices with sulfonium centers can provide a precise, biocompatible, and effective co-delivery vaccine platform for tumor immunotherapy and prevention.

Cyanidin chloride modestly protects Caco-2 cells from ZnO nanoparticle exposure probably through the induction of autophagy.

Recent studies suggest that phytochemicals, as part of the food matrix, might alter the toxicity of nanoparticles (NPs); however, relatively few studies have investigated the impact of anthocyanidins on the toxicity of NPs to cells lining the gastrointestinal tract. Therefore, this study used cyanidin chloride (CC) as the model for anthocyanidins and investigated the effects of CC on the toxicity of ZnO or Ag NPs to Caco-2 cells. Exposure to ZnO but not Ag NPs significantly induced cytotoxicity. The presence of CC, but not its analog quercetin (Qu), modestly protected Caco-2 cells from ZnO NP exposure. However, the intracellular superoxide, Zn ions, or release of interleukin-8 after ZnO NP exposure were not significantly affected by the presence of CC. Rather, CC promoted the expression of autophagic genes ATG5, ATG7, and BECN1 as well as the ratio of LC3-II/I after exposure to ZnO NPs. Meanwhile, the presence of autophagic inhibitors (chloroquine, NH4Cl, bafilomycin A1) significantly promoted the cytotoxicity of ZnO NPs and inhibited the cytoprotective effects of CC. In conclusion, these data suggest that CC could modestly protect Caco-2 cells from ZnO NP exposure, probably through the induction of autophagy.

The presence of oleate stabilized ZnO nanoparticles (NPs) and reduced the toxicity of aged NPs to Caco-2 and HepG2 cells.

The presence of food components may alter the colloidal aspects and toxicity of nanoparticles (NPs). In this study, the toxicity of ZnO NPs to Caco-2 and HepG2 cells was assessed, with the emphasis on the interactions between ZnO NPs and oleate (OA). The presence of OA increased UV-Vis spectra and hydrodynamic sizes, decreased Zeta potential, and markedly reduced the release of Zn ions from the dissolution of ZnO NPs, which combined indicated that OA could coat ZnO NPs and stabilize ZnO NPs. Exposure to ZnO NPs significantly induced cytotoxicity to Caco-2 and HepG2 cells, associated with increased intracellular Zn ions but not superoxide. When OA was added to the freshly prepared ZnO NP suspensions, the cytotoxicity, intracellular Zn ions and superoxide induced by ZnO NPs were not significantly affected. However, when ZnO NPs were aged for 24 h with the presence of OA, the cytotoxicity of ZnO NPs to Caco-2 and HepG2 cells was significantly reduced, associated with a reduction of intracellular Zn ions. The results from this study suggested that the presence of OA could increase colloidal stability of ZnO NPs and consequently reduce the toxicity of ZnO NPs after aging associated with reduced accumulation of intracellular Zn ions.

A review of endoplasmic reticulum (ER) stress and nanoparticle (NP) exposure.

Understanding the mechanism of nanoparticle (NP) induced toxicity is important for nanotoxicological and nanomedicinal studies. Endoplasmic reticulum (ER) is a crucial organelle involved in proper protein folding. High levels of misfolded proteins in the ER could lead to a condition termed as ER stress, which may ultimately influence the fate of cells and development of human diseases. In this review, we summarized studies about effects of NP exposure on ER stress. A variety of NPs, especially metal-based NPs, could induce morphological changes of ER and activate ER stress pathway both in vivo and in vitro. In addition, modulation of ER stress by chemicals has been shown to alter the toxicity of NPs. These studies in combination suggested that ER stress could be the mechanism responsible for NP induced toxicity. Meanwhile, nanomedicinal studies also used ER stress inducing NPs or NPs loaded with ER stress inducer to selectively induce ER stress mediated apoptosis in cancer cells for cancer therapy. In contrast, alleviation of ER stress by NPs has also been shown as a strategy to cure metabolic diseases. In conclusion, exposure to NPs may modulate ER stress, which could be a target for future nanotoxicological and nanomedicinal studies.