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.

Restoration of Sinusoid Fenestrae Followed by Targeted Nanoassembly Delivery of an Anti-Fibrotic Agent Improves Treatment Efficacy in Liver Fibrosis.

During the onset of liver fibrosis, capillarized liver sinusoidal endothelial cells (LSECs) limit substance exchange between the blood and the Disse space, further accelerating hepatic stellate cell (HSCs) activation and fibrosis progression. Limited accessibility of therapeutics to the Disse space is often overlooked and remains a major bottleneck for HSCs-targeted therapy in liver fibrosis. Here, an integrated systemic strategy for liver fibrosis treatment is reported, utilizing pretreatment with the soluble guanylate cyclase stimulator, riociguat, followed by insulin growth factor 2 receptor-mediated targeted delivery of the anti-fibrosis agent, JQ1, via peptide-nanoparticles (IGNP-JQ1).

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.

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.

Functional Immune Cell-Derived Exosomes Engineered for the Trilogy of Radiotherapy Sensitization.

The limited efficacy of radiotherapy leads to radio-resistance and high rates of tumor recurrence and metastasis, which is caused by tumor hypoxia, rapid DNA damage repair, and especially the suppressive immune microenvironment of tumor. Lots of immune cell-derived exosomes can regulate antitumor immunity, but their application in enhancing radiotherapy is rarely studied. Herein, as a model of concept, M1 macrophage-derived exosomes (M1Exos) is engineered as effective radiotherapy sensitizers, realizing the trilogy of radiotherapy sensitization: 1) M1Exos is engineered to express catalases on the inside of membrane, which can effectively relieve tumor hypoxia, and enhance DNA damage.

Antigen-bearing outer membrane vesicles as tumour vaccines produced in situ by ingested genetically engineered bacteria.

The complex gastrointestinal environment and the intestinal epithelial barrier constrain the design and effectiveness of orally administered tumour vaccines. Here we show that outer membrane vesicles (OMVs) fused to a tumour antigen and produced in the intestine by ingested genetically engineered bacteria function as effective tumour vaccines in mice. We modified Escherichia coli to express, under the control of a promoter induced by the monosaccharide arabinose, a specific tumour antigen fused with the protein cytolysin A on the surface of OMVs released by the commensal bacteria.

Rapid Surface Display of mRNA Antigens by Bacteria-Derived Outer Membrane Vesicles for a Personalized Tumor Vaccine.

Therapeutic mRNA vaccination is an attractive approach to trigger antitumor immunity. However, the mRNA delivery technology for customized tumor vaccine is still limited. In this work, bacteria-derived outer membrane vesicles (OMVs) are employed as an mRNA delivery platform by genetically engineering with surface decoration of RNA binding protein, L7Ae, and lysosomal escape protein, listeriolysin O (OMV-LL).

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).

Biomimetic Nanoparticles Carrying a Repolarization Agent of Tumor-Associated Macrophages for Remodeling of the Inflammatory Microenvironment Following Photothermal Therapy.

The complete regression of residual tumors after photothermal therapy (PTT) depends on the activation and recognition of the immune system. However, the inevitable local inflammation after PTT in residual tumor recruits abundant abnormal immune cells, especially the tumor-associated macrophages (TAMs) which further promote immune escape and survival of the remaining tumor cells, resulting in the tumor recurrence and progression. To solve this problem, herein we explored biomimetic nanoparticles carrying repolarization agent of TAMs to remodel the post-PTT inflammatory microenvironment.

Melanin-Like Nanomedicine in Photothermal Therapy Applications.

Photothermal therapy (PTT) mediated by nanomaterial has become an attractive tumor treatment method due to its obvious advantages. Among various nanomaterials, melanin-like nanoparticles with nature biocompatibility and photothermal conversion properties have attracted more and more attention. Melanin is a natural biological macromolecule widely distributed in the body and displays many fascinating physicochemical properties such as excellent biocompatibility and prominent photothermal conversion ability.

Synthesis of new tetracyclic benzodiazepine-fused isoindolinones using recyclable mesoporous silica nanoparticles.

Pseudo natural products (NPs) feature structural novelty and diversity and thus are a new source of lead compounds for drug discovery. We first report the mesoporous silica nanoparticles (MSNs)-catalyzed de novo combination of benzodiazepine and isoindolinone, giving tetracyclic benzodiazepine-fused isoindolinone pseudo natural products (21 examples, 55-91% yields). The work also demonstrates that MSNs are efficient acidic catalysts for multi-component reactions.

Rapid Capture and Nondestructive Release of Extracellular Vesicles Using Aptamer-Based Magnetic Isolation.

Extracellular vesicles (EVs) play important roles in cell-cell communication by transferring cargo proteins and nucleic acids between cells. Due to their small size (50-150 nm) and low density, rapid capture and nondestructive release of EVs remains a technical challenge which significantly hinders study of their biofunction and biomedical application. To address this issue, we designed a DNA aptamer-based system that enabled rapid capture and nondestructive release of EVs in 90 min with similar isolation efficiency to ultracentrifugation (around 78%).