Intelligent Responsive Nanoparticles with Multilevel Triggered Drug Penetration for Tumor Photochemotherapy.

Nanomedicines have contradictory size requirements to overcome systemic barriers and penetrate the tumor extracellular matrix (ECM). Larger-sized nanoparticles (50-200 nm) exhibit prolonged blood circulation half-life and improved tumor enrichment, while small-sized nanoparticles (4-20 nm) easily penetrate deep tumor tissues. Therefore, the development of intelligent responsive nanomedicine systems can not only increase nanodrug tumor accumulation but also improve their penetration into the ECM.

Modular-designed engineered bacteria for precision tumor immunotherapy via spatiotemporal manipulation by magnetic field.

Micro-nano biorobots based on bacteria have demonstrated great potential for tumor diagnosis and treatment. The bacterial gene expression and drug release should be spatiotemporally controlled to avoid drug release in healthy tissues and undesired toxicity. Herein, we describe an alternating magnetic field-manipulated tumor-homing bacteria developed by genetically modifying engineered Escherichia coli with FeO@lipid nanocomposites.

Nanoscale Organization of TRAIL Trimers using DNA Origami to Promote Clustering of Death Receptor and Cancer Cell Apoptosis.

Through inducing death receptor (DR) clustering to activate downstream signaling, tumor necrosis factor related apoptosis inducing ligand (TRAIL) trimers trigger apoptosis of tumor cells. However, the poor agonistic activity of current TRAIL-based therapeutics limits their antitumor efficiency. The nanoscale spatial organization of TRAIL trimers at different interligand distances is still challenging, which is essential for the understanding of interaction pattern between TRAIL and DR.

Site-Specific Modification of Virus-Like Particles for Exogenous Tumor Antigen Display and Minimizing Preexisting Immunity.

The widespread preexisting immunity against virus-like particles (VLPs) seriously limits the applications of VLPs as vaccine vectors. Enabling technology for exogenous antigen display should not only ensure the assembly ability of VLPs and site-specific modification, but also consider the effect of preexisting immunity on the behavior of VLPs in vivo. Here, combining genetic code expansion technique and synthetic biology strategy, a site-specific modification method for hepatitis B core (HBc) VLPs via incorporating azido-phenylalanine into the desired positions is described.

Normalizing the Immune Macroenvironment via Debulking Surgery to Strengthen Tumor Nanovaccine Efficacy and Eliminate Metastasis.

In tumor nanovaccines, nanocarriers enhance the delivery of tumor antigens to antigen-presenting cells (APCs), thereby ensuring the robust activation of tumor antigen-specific effector T-cells to kill tumor cells. Through employment of their high immunogenicity and nanosize, we have developed a "Plug-and-Display" delivery platform on the basis of bacterial outer membrane vesicles (OMVs) for tumor nanovaccines (NanoVac), which can rapidly display different tumor antigens and efficiently eliminate lung metastases of melanoma. In this study, we first upgraded the NanoVac to increase their antigen display efficiency.

Lipid-Peptide-mRNA Nanoparticles Augment Radioiodine Uptake in Anaplastic Thyroid Cancer.

Restoring sodium iodide symporter (NIS) expression and function remains a major challenge for radioiodine therapy in anaplastic thyroid cancer (ATC). For more efficient delivery of messenger RNA (mRNA) to manipulate protein expression, a lipid-peptide-mRNA (LPm) nanoparticle (NP) is developed. The LPm NP is prepared by using amphiphilic peptides to assemble a peptide core and which is then coated with cationic lipids.

Probiotic-Inspired Nanomedicine Restores Intestinal Homeostasis in Colitis by Regulating Redox Balance, Immune Responses, and the Gut Microbiome.

Microbiota-based therapeutics offer innovative strategies to treat inflammatory bowel diseases (IBDs). However, the poor clinical outcome so far and the limited flexibility of the bacterial approach call for improvement. Inspired by the health benefits of probiotics in alleviating symptoms of bowel diseases, bioartificial probiotics are designed to restore the intestinal microenvironment in colitis by regulating redox balance, immune responses, and the gut microbiome.

Efficacy of pp65-specific TCR-T cell therapy in treating cytomegalovirus infection after hematopoietic stem cell transplantation.

Cytomegalovirus (CMV) infection remains a major cause of mortality after hematopoietic stem cell transplantation (HSCT). Current treatments, including antiviral drugs and adoptive cell therapy with CMV-specific cytotoxic T lymphocytes (CTLs), only show limited benefits in patients. T-cell receptor (TCR)-T cell therapy offers a promising option to treat CMV infections.

Engineered Bacterial Outer Membrane Vesicles as Controllable Two-Way Adaptors to Activate Macrophage Phagocytosis for Improved Tumor Immunotherapy.

The most immune cells infiltrating tumor microenvironment (TME), tumor-associated macrophages (TAMs) closely resemble immunosuppressive M2-polarized macrophages. Moreover, tumor cells exhibit high expression of CD47 "don't eat me" signal, which obstructs macrophage phagocytosis. The precise and efficient activation of TAMs is a promising approach to tumor immunotherapy; however, re-education of macrophages remains a challenge.

A novel adoptive synthetic TCR and antigen receptor (STAR) T-Cell therapy for B-Cell acute lymphoblastic leukemia.

We developed a T-cell-receptor (TCR) complex-based chimeric antigen receptor (CAR) named Synthetic TCR and Antigen Receptor (STAR). Here, we report pre-clinical and phase I clinical trial data (NCT03953599) of this T-cell therapy for refractory and relapsed (R/R) B-cell acute lymphoblastic leukemia (B-ALL) patients. STAR consists of two protein modules each containing an antibody light or heavy chain variable region and TCR α or β chain constant region fused to the co-stimulatory domain of OX40.

Antigen Capture and Immune Modulation by Bacterial Outer Membrane Vesicles as In Situ Vaccine for Cancer Immunotherapy Post-Photothermal Therapy.

Tumor antigens released from tumor cells after local photothermal therapy (PTT) can activate the tumor-specific immune responses, which are critical for eliminating the residual lesions and distant metastases. However, the limited recognition efficiency of released tumor antigens by the immune system and the immunosuppressive microenvironment lead to ineffective antitumor immunity. Here, an in situ multifunctional vaccine based on bacterial outer membrane vesicles (OMVs, 1-MT@OMV-Mal) is developed by surface conjunction of maleimide groups (Mal) and interior loading with inhibitor of indoleamine 2, 3-dioxygenase (IDO), 1-methyl-tryptophan (1-MT).

Personalized cancer vaccines from bacteria-derived outer membrane vesicles with antibody-mediated persistent uptake by dendritic cells.

Nanocarriers with intrinsic immune adjuvant properties can activate the innate immune system while delivering tumor antigen, thus efficiently facilitating antitumor adaptive immunity. Bacteria-derived outer membrane vesicles (OMVs) are an excellent candidate due to their abundance of pathogen associated molecular patterns. However, during the uptake of OMVs by dendritic cells (DCs), the interaction between lipopolysaccharide and toll-like receptor 4 induces rapid DC maturation and uptake blockage, a phenomenon we refer to as "maturation-induced uptake obstruction" (MUO).

Nanotechnology-empowered vaccine delivery for enhancing CD8 T cells-mediated cellular immunity.

After centuries of development, using vaccination to stimulate immunity has become an effective method for prevention and treatment of a variety of diseases including infective diseases and cancers. However, the tailor-made efficient delivery system for specific antigens is still urgently needed due to the low immunogenicity and stability of antigens, especially for vaccines to induce CD8 T cells-mediated cellular immunity. Unlike B cells-mediated humoral immunity, CD8 T cells-mediated cellular immunity mainly aims at the intracellular antigens from microorganism in virus-infected cells or genetic mutations in tumor cells.

Enhancing CAR-T cell efficacy in solid tumors by targeting the tumor microenvironment.

Chimeric antigen receptor (CAR)-T cell therapy has achieved successful outcomes against hematological malignancies and provided a new impetus for treating solid tumors. However, the efficacy of CAR-T cells for solid tumors remains unsatisfactory. The tumor microenvironment has an important role in interfering with and inhibiting the effector function of immune cells, among which upregulated inhibitory checkpoint receptors, soluble suppressive cytokines, altered chemokine expression profiles, aberrant vasculature, complicated stromal composition, hypoxia and abnormal tumor metabolism are major immunosuppressive mechanisms.

Chimeric STAR receptors using TCR machinery mediate robust responses against solid tumors.

Chimeric antigen receptor T (CAR-T) cell therapies have demonstrated high response rate and durable disease control for the treatment of B cell malignancies. However, in the case of solid tumors, CAR-T cells have shown limited efficacy, which is partially attributed to intrinsic defects in CAR signaling. Here, we construct a double-chain chimeric receptor, termed as synthetic T cell receptor (TCR) and antigen receptor (STAR), which incorporates antigen-recognition domain of antibody and constant regions of TCR that engage endogenous CD3 signaling machinery.

Bacterial Outer Membrane Vesicles Presenting Programmed Death 1 for Improved Cancer Immunotherapy Immune Activation and Checkpoint Inhibition.

Natural, extracellular membrane vesicles secreted by Gram-negative bacteria, outer membrane vesicles (OMVs), contain numerous pathogen-associated molecular patterns which can activate systemic immune responses. Previous studies have shown that OMVs induce strong IFN-γ- and T cell-mediated anti-tumor effects in mice. However, IFN-γ is known to upregulate immunosuppressive factors in the tumor microenvironment, especially the immune checkpoint programmed death 1 ligand 1 (PD-L1), which may hamper T cell function and limit immunotherapeutic effectiveness.

Combination of tumour-infarction therapy and chemotherapy via the co-delivery of doxorubicin and thrombin encapsulated in tumour-targeted nanoparticles.

Drugs that induce thrombosis in the tumour vasculature have not resulted in long-term tumour eradication owing to tumour regrowth from tissue in the surviving rim of the tumour, where tumour cells can derive nutrients from adjacent non-tumoral blood vessels and tissues. Here, we report the performance of a combination of tumour-infarction therapy and chemotherapy, delivered via chitosan-based nanoparticles decorated with a tumour-homing peptide targeting fibrin-fibronectin complexes overexpressed on tumour-vessel walls and in tumour stroma, and encapsulating the coagulation-inducing protease thrombin and the chemotherapeutic doxorubicin. Systemic administration of the nanoparticles into mice and rabbits bearing subcutaneous or orthotopic tumours resulted in higher tumour growth suppression and decreased tumour recurrence than nanoparticles delivering only thrombin or doxorubicin, with histological and haematological analyses indicating an absence of detectable toxicity.

CXCR2-modified CAR-T cells have enhanced trafficking ability that improves treatment of hepatocellular carcinoma.

Unlike hematological malignancies, solid tumors have proved to be less susceptible to chimeric antigen receptor (CAR)-T cell therapy, which is partially caused by reduced accumulation of therapeutic T cells in tumor site. Since efficient trafficking is the precondition and pivotal step for infused CAR-T cells to exhibit their anti-tumor function, strategies are highly needed to improve the trafficking ability of CAR-T cells for solid tumor treatment. Here, based on natural lymphocyte chemotaxis theory and characteristics of solid tumor microenvironments, we explored the possibility of enhancing CAR-T cell trafficking by using chemokine receptors.

A Bioinspired Nanoprobe with Multilevel Responsive T -Weighted MR Signal-Amplification Illuminates Ultrasmall Metastases.

Metastasis remains the major cause of death in cancer patients. Thus, there is a need to sensitively detect tumor metastasis, especially ultrasmall metastasis, for early diagnosis and precise treatment of cancer. Herein, an ultrasensitive T -weighted magnetic resonance imaging (MRI) contrast agent, UMFNP-CREKA is reported.

Engineered Nanoplatelets for Targeted Delivery of Plasminogen Activators to Reverse Thrombus in Multiple Mouse Thrombosis Models.

Rapid cut-off of blood supply in diseases involving thrombosis is a major cause of morbidity and mortality worldwide. However, the current thrombolysis strategies offer limited results due to the therapeutics' short half-lives, low targeting ability, and unexpected bleeding complications. Inspired by the innate roles of platelets in hemostasis and pathological thrombus, platelet membrane-camouflaged polymeric nanoparticles (nanoplatelets) are developed for targeting delivery of the thrombolytic drug, recombinant tissue plasminogen activator (rt-PA), to local thrombus sites.

Engineering Biomimetic Platesomes for pH-Responsive Drug Delivery and Enhanced Antitumor Activity.

Biomimetic camouflage, i.e., using natural cell membranes for drug delivery, has demonstrated advantages over synthetic materials in both pharmacokinetics and biocompatibility, and so represents a promising solution for the development of safe nanomedicine.