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Chronic antigenic stimulation can trigger the differentiation of antigen-experienced CD4+ T cells into T regulatory type 1 (TR1) cells, a subset of interleukin-10-producing Treg cells that do not express FOXP3. The identities of the progenitor(s) and transcriptional regulators of this T-cell subset remain unclear. Here, we show that the peptide-major histocompatibility complex class II (pMHCII) monospecific immunoregulatory T-cell pools that arise in vivo in different genetic backgrounds in response to pMHCII-coated nanoparticles (pMHCII-NPs) are invariably comprised of oligoclonal subpools of T follicular helper (TFH) and TR1 cells with a nearly identical clonotypic composition but different functional properties and transcription factor expression profiles. Pseudotime analyses of scRNAseq data and multidimensional mass cytometry revealed progressive downregulation and upregulation of TFH and TR1 markers, respectively. Furthermore, pMHCII-NPs trigger cognate TR1 cell formation in TFH cell-transfused immunodeficient hosts, and T-cell-specific deletion of Bcl6 or Irf4 blunts both the TFH expansion and TR1 formation induced by pMHCII-NPs. In contrast, deletion of Prdm1 selectively abrogates the TFH-to-TR1 conversion. Bcl6 and Prdm1 are also necessary for anti-CD3 mAb-induced TR1 formation. Thus, TFH cells can differentiate into TR1 cells in vivo, and BLIMP1 is a gatekeeper of this cellular reprogramming event.

Peptide MHC class II–based (pMHCII-based) nanomedicines trigger the formation of multicellular regulatory networks by reprogramming autoantigen-experienced CD4(+) T cells into autoimmune disease–suppressing T regulatory type 1 (TR1) cells. We have shown that pMHCII-based nanomedicines displaying liver autoimmune disease–relevant yet ubiquitously expressed antigens can blunt various liver autoimmune disorders in a non–disease-specific manner without suppressing local or systemic immunity against infectious agents or cancer. Here, we show that such ubiquitous autoantigen-specific T cells are also awakened by extrahepatic tissue damage and that the corresponding TR1 progeny can suppress experimental autoimmune encephalomyelitis (EAE) and pancreatic β cell autoreactivity. In mice having EAE, nanomedicines displaying either ubiquitous or CNS-specific epitopes triggered the formation and expansion of cognate TR1 cells and their recruitment to the CNS-draining lymph nodes, sparing their liver-draining counterparts. Surprisingly, in mice having both liver autoimmunity and EAE, liver inflammation sequestered these ubiquitous or even CNS-specific TR1 cells away from the CNS, abrogating their antiencephalitogenic activity. In these mice, only the ubiquitous antigen-specific TR1 cells suppressed liver autoimmunity. Thus, the scope of antigen spreading in autoimmune disorders is larger than previously anticipated, involving specificities expected to be silenced by mechanisms of tolerance; the regulatory activity, but not the retention of autoreactive TR1 cells, requires local autoantigen expression.

Nanoparticles (NPs) coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHCs) can blunt autoimmune diseases by re-programming cognate effector T-lymphocytes into disease-suppressing regulatory T-cells, followed by massive expansion. Here, a method to quantify the absolute amounts of the active drug product is developed, to understand the relationship between bioavailability and pharmacodynamics. Incubation with plasma results in the formation of a protein corona that stabilizes the directional pMHC coat, shielding it from proteolysis or anti-drug antibody recognition, without any appreciable loss in biological potency. A quantitative method that harnesses these features indicates that the half-life of these compounds in the circulation and organs is an order of magnitude shorter (minutes vs. hours) than that measured using commonly-used semi-quantitative methods. Extensive transmission electron microscopy-based organ scanning and flow cytometry-based enumeration of pMHCII-NP capturing cells confirmed that these compounds are rapidly captured (within 1 min) by liver sinusoidal endothelial cells, Kupffer cells, splenic phagocytes and cognate T-cells, leading to a fast decline in the circulation. Therefore, the powerful pharmacodynamic effects of these compounds are dissociated from long bioavailability, implying a hit-and-run event. Collectively, these data provide a detailed view of the life-cycle of a nanoimmunomedicine, and suggest that the real half-lives of intact nanomedicines may be much shorter than those estimated using indirect approaches.

Peptide-major histocompatibility complex class II (pMHCII)-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by re-programming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells. Here, we show that single pMHCII-based nanomedicines displaying epitopes from mitochondrial, endoplasmic reticulum or cytoplasmic antigens associated with primary biliary cholangitis (PBC) or autoimmune hepatitis (AIH) can broadly blunt PBC, AIH and Primary Sclerosing Cholangitis in various murine models in an organ- rather than disease-specific manner, without suppressing general or local immunity against infection or metastatic tumors. Therapeutic activity is associated with cognate TR1 cell formation and expansion, TR1 cell recruitment to the liver and draining lymph nodes, local B-regulatory cell formation and profound suppression of the pro-inflammatory capacity of liver and liver-proximal myeloid dendritic cells and Kupffer cells. Thus, autoreactivity against liver-enriched autoantigens in liver autoimmunity is not disease-specific and can be harnessed to treat various liver autoimmune diseases broadly., Immune response against tissue-specific antigens is a hallmark of autoimmunity. Here the authors show that a single autoantigen-based nanomedicine can ameliorate pathology in a broad range of liver autoimmunity models without impairing host defenses, suggesting organ-wide tolerization.

Nanoparticles in polluted air or aerosolized drug nanoparticles predominantly settle in the alveolar lung. Here, we describe a novel, highly effective pathway for the particles to cross the alveolar epithelium and reach the lymph and bloodstream. Amorphous silica nanoparticles, suspended in perfluorocarbon, were instilled into the lungs of mice for intravital microscopy. Particles formed agglomerates that settled on the alveolar wall, half of which were removed from the lung within 30 minutes. TEM histology showed agglomerates in stages of crossing the alveolar epithelium, in large compartments inside the epithelial cells and crossing the basal membrane into the interstitium. This pathway is consistent with published kinetic studies in rats and mice, using a host of (negatively) charged and polar nanoparticles.

The uphill energy transfer in photosystems implies input energy at higher wavelength leading to energy output at lower wavelength. Briefly, energy is uphill transported from photosystem I (PSI) to photosystem II (PSII), the latter having a lower wavelength emission. This uphill energy transport involves absorption of thermal energy from the surroundings. While such cooling effects have been reported in laser systems we report for the first time a white light driven cooling in thylakoid suspension. The cooling of the surrounding medium by appropriate illumination was illustrated using thermal measurements. Again cooling is inhibited by agents like 3-(3,4-Dichlorophenyl)-1,1-dimethylurea,that block the linear electron flow between the photocenters, implying a dependence of the cooling on interplay between such centers. Furthermore, it is possible to modulate the cooling pattern by addition of external agents like nanopaticles, some favoring further cooling (e.g., Ag nanoparticle) and some like Au or chlorophyll nanoparticles, showing insignificant or even reverse trends. Interestingly, the cooling is invariably associated with the 77K spectra of the thylakoid suspension. With reference to the dark control, an agent causing cooling always increases PSII to PSI ratio and vice versa i.e.,the uphill energy transport. Importantly, the cooling effect, apart from its import role in plant physiology can be exploited artificially for energy saving in post-harvest or food preservation.

The design of nanovaccines capable of triggering effective antitumor immunity requires an understanding of how the immune system senses and responds to threats, including pathogens and tumors. Equally important is an understanding of the mechanisms employed by tumor cells to evade immunity and an appreciation of the deleterious effects that antitumor immune responses can have on tumor growth, such as by skewing tumor cell composition toward immunologically silent tumor cell variants. The immune system and tumors engage in a tug-of-war driven by competition where promoting antitumor immunity or tumor cell death alone may be therapeutically insufficient. Nanotechnology affords a unique opportunity to develop therapeutic compounds than can simultaneously tackle both aspects, favoring tumor eradication. Here, we review the current status of nanoparticle-based immunotherapeutic strategies for the treatment of cancer, ranging from antigen/adjuvant delivery vehicles (to professional antigen-presenting cell types of the immune system) to direct tumor antigen-specific T-lymphocyte-targeting compounds and their combinations thereof.

Regulatory T cells hold promise as targets for therapeutic intervention in autoimmunity, but approaches capable of expanding antigen-specific regulatory T cells in vivo are currently not available. Here we show that systemic delivery of nanoparticles coated with autoimmune-disease-relevant peptides bound to major histocompatibility complex class II (pMHCII) molecules triggers the generation and expansion of antigen-specific regulatory CD4(+) T cell type 1 (TR1)-like cells in different mouse models, including mice humanized with lymphocytes from patients, leading to resolution of established autoimmune phenomena. Ten pMHCII-based nanomedicines show similar biological effects, regardless of genetic background, prevalence of the cognate T-cell population or MHC restriction. These nanomedicines promote the differentiation of disease-primed autoreactive T cells into TR1-like cells, which in turn suppress autoantigen-loaded antigen-presenting cells and drive the differentiation of cognate B cells into disease-suppressing regulatory B cells, without compromising systemic immunity. pMHCII-based nanomedicines thus represent a new class of drugs, potentially useful for treating a broad spectrum of autoimmune conditions in a disease-specific manner.

Nano-medical approaches to develop drugs have attracted much attention in different arenas to design nanoparticle conjugates for better efficacy of the potential bio-molecules. A group of promising candidates of this category would be venom-toxins of animal origin of potential medicinal value. Traditional systems of medicine as well as folklores mention the use of venom-toxins for the treatment of various diseases. Research has led to scientific validation of medicinal applications of venoms-toxins and many active constituents derived from venoms-toxins are already in clinical use or under clinical trial. Nanomedicine is an emerging field of medicine where nanotechnology is used to develop molecules of nano-scale dimension, so that these molecules can be taken up by the cells more easily and have better efficacy, as compared to large molecules that may tend to get eliminated. This review will focus on some of the potential venoms and toxins along with nanoparticle conjugated venom-toxins of snakes, amphibians, scorpions and bees, etc., for possible therapeutic clues against emerging diseases.