Nanoscale Precise Editing of Multiple Immune Stimulating Ligands on DNA Origami for T Cell Activation and Cell-Based Cancer Immunotherapy

The spatial arrangement of activating ligands is known to have great influence on T cell activation.However,independently studying each ligand’s spatial organization parameter that affects T cell activation remains a great challenge.Here,with DNA origami,we precisely organized the CD3ɛantibodies simulating T cell receptor(TCR)ligands and CD28 antibodies simulating co-stimulatory ligands to interrogate the independent role of TCR-ligand spacing and local copy numbers as well as the spacing between TCR ligands and co-stimulatory ligands on T cell activation.We found that T cell activation benefited fromlocally concentrated TCR ligands with a shorter spacing and was maximized by an∼38 nm spacing between TCR ligands and co-stimulatory ligands.The T cell expander constructed based on our findings could efficiently expand CD8+T cells for tumor immunotherapy.Thus,the DNA nanostructurebased ligands’precise arrangement can be a unique tool in studying immune cell activations and cellbased immunotherapies.

Dapsone hypersensitivity syndrome

Dapsone hypersensitivity syndrome(DHS)was first reported by Lowe and Smith[1]in 1949 in Nigeria and was termed“dapsone syndrome”by Allday and Barnes[2]in 1951.DHS is a drug-induced hypersensitivity syndrome(DIHS)caused by dapsone 404’-diaminodiphenylsulfone(DDS).DHS is characterized by fever,rash,lymphadenopathy,and hepatitis,which usually develop after patients receive DDS for 5 to 6 weeks.Epidemiological studies have estimated DHS prevalence and fatality rates of 1.4%and 9.9%,respectively.[3]Until recently,the“wait and see”approach was used for patients with suspected DHS.Herein,we review recent developments in DHS research,focusing on its etiology,pathogenesis,diagnosis,and prevention,to make DDS a safer medication for most of the population through the prospective exclusion of susceptible patients before DDS administration.

Precise regulation of intermembrane spacing with DNA nanojunctions for enhanced T-cell receptor triggering

It is well known that adaptive immunity involving T cells plays a crucial role in combating many diseases.T-cell activation is initiated by the engagement of T-cell receptors(TCRs)to peptide-loaded major histocompatibility complexes(p MHCs)on antigen-presenting cells(APCs),which triggers a cascade of signaling events that ultimately lead to T-cell activation[1].

Sonodynamic therapy with immune modulatable two-dimensional coordination nanosheets for enhanced anti-tumor immunotherapy

Ultrasound with deep penetration depth and high security could be adopted in sonodynamic therapy(SDT)by activating sonosensitizers to generate cytotoxic reactive oxygen species(ROS).Herein,two-dimensional(2D)coordination nanosheets composed of Zn^(2+)and Tetrakis(4-carboxyphenyl)porphyrin(TCPP)are fabricated.While exhibiting greatly enhanced ultrasoundtriggered ROS generation useful for noninvasive SDT,such Zn-TCPP 2D nanosheets show high loading capacity of oligodeoxynudeotides such as cytosine—phosphorothioate-guanine(CpG),which is a potent toll like receptor 9(TLR9)agonist useful in activating immune responses.Highly effective SD T of primary tumors could release tumor-associated antigens,which working together with Zn-TCPP/CpG adjuvant nanosheets could function like whole-tumor-cell vaccines and trigger tumor-specific immune responses.Interestingly,ultrasound itself could strengthen anti-tumor immune responses by improving the tumor-infiltration of T cells and limiting regulatory T cells in the tumor microenvironment.Thus,SDT using Zn-TCPP/CpG nanosheets after destruction of primary tumors could induce potent antitumor immune responses to inhibit distant abscopal tumors without direct SD T treatment.Moreover,SDT with Zn-TCPP/CpG could trigger strong immunological memory effects to inhibit cancer recurrence after elimination of primary tumors.Therefore,the 2D coordination nanosheet may be a promising platform to deliver potent SDT-triggered immunotherapy for highly effective cancer treatment.

Biological membrane derived nanomedicines for cancer therapy

The development of nanomedicine systems for applications in cancer therapies has been widely explored in the last decade.With inherent biocompatibility,nanomedicine devices derived from biological membranes have shown many unique advantages compared with traditional artificial nanomaterials for biomedical applications.Herein,we present a comprehensive review of the recent development of cell membrane derived nanomedicines in cancer treatment.We firstly outline the advantages of biological membranes in nanomedicine design derived from their intrinsic characteristics,and then discuss the applications of biological membrane derived nanomedicines.For the first major category of membrane-derived nanomedicine,synthetic nanoparticles are usually camouflaged with cell membranes to acquire additional functionalities.The other type of membrane-based nanomedicine is directly using the engineered cell membrane-derived vesicles or nanovesicles secreted by cells for tumor treatment.At last,we discuss the challenges of membrane-derived nanomedicines towards future clinical applications,following with perspectives on possible solutions to the current problems.