CCL9/CCR1 axis-driven chemotactic nanovesicles for attenuating metastasis of SMAD4-deficient colorectal cancer by trapping TGF-.

SMAD4 deficiency in colorectal cancer (CRC) is highly correlated with liver metastasis and high mortality, yet there are few effective precision therapies available. Here, we show that CCR1-granulocytic myeloid-derived suppressor cells (G-MDSCs) are highly infiltrated in SMAD4-deficient CRC CCL15/CCR1 and CCL9/CCR1 axis in clinical specimens and mouse models, respectively. The excessive TGF-, secreted by tumor-infiltrated CCR1-G-MDSCs, suppresses the immune response of cytotoxic T lymphocytes (CTLs), thus facilitating metastasis.

Mitoxantrone Combined with Engineered TRAIL-Nanovesicles for Enhanced Cancer Immunotherapy Via Converting Apoptosis into Pyroptosis.

Pyroptosis, a highly inflammatory form of programmed cell death, has emerged as a promising target for cancer immunotherapy. However, in the context of pyroptosis execution, while both caspase-3 and GSDME are essential, it is noteworthy that GSDME is frequently under-expressed in cold tumors. To overcome this limitation, engineered cellular nanovesicles (NVs) presenting TRAIL on their membranes (NV) are developed to trigger the upregulation of cleaved caspase-3.

Hybrid biomineralized nanovesicles to enhance inflamed lung biodistribution and reduce side effect of glucocorticoid for ARDS therapy.

Acute respiratory distress syndrome (ARDS) is a critical illness characterized by severe lung inflammation. Improving the delivery efficiency and achieving the controlled release of anti-inflammatory drugs at the lung inflammatory site are major challenges in ARDS therapy. Taking advantage of the increased pulmonary vascular permeability and a slightly acidic-inflammatory microenvironment, pH-responsive mineralized nanoparticles based on dexamethasone sodium phosphate (DSP) and Ca were constructed.

Colon Targeting pH-Responsive Coacervate Microdroplets for Treatment of Ulcerative Colitis.

Ulcerative colitis (UC), an immune-mediated chronic inflammatory disease, drastically impacts patients' quality of life and increases their risk of colorectal cancer worldwide. However, effective oral targeted delivery and retention of drugs in colonic lesions are still great challenges in the treatment of UC. Coacervate microdroplets, formed by liquid-liquid phase separation, are recently explored in drug delivery as the simplicity in fabrication, spontaneous enrichment on small molecules and biological macromolecules, and high drug loading capacity.

Engineered Biomimetic Nanovesicles Based on Neutrophils for Hierarchical Targeting Therapy of Acute Respiratory Distress Syndrome.

Acute Respiratory Distress Syndrome (ARDS) is a clinically severe respiratory disease that causes severe medical and economic burden. To improve therapeutic efficacy, effectively targeting delivery to the inflamed lungs and inflamed cells remains an ongoing challenge. Herein, we designed engineered biomimetic nanovesicles (DHA@ANeu-DDAB) by fusion of lung-targeting functional lipid, neutrophil membrane containing activated β integrins, and the therapeutic lipid, docosahexaenoic acid (DHA).

Discovery of 5-(Pyrimidin-2-ylamino)-1-indole-2-carboxamide Derivatives as Nur77 Modulators with Selective and Potent Activity Against Triple-Negative Breast Cancer.

The orphan nuclear receptor Nur77 has been validated as a potential drug target for treating breast cancer. Therefore, focusing on the SAR study of the lead ( = 354 nM), we found the active compound which exhibited improved Nur77-binding capability ( = 91 nM) and excellent antiproliferative activities against breast cancer cell lines. Interestingly, acted as a potent and selective Nur77 antagonist, displaying good potency against triple-negative breast cancer (TNBC) cell lines but did not inhibit human normal breast cancer cell line MCF-10A (SI > 20).

Precise delivery of celastrol by PEGylated aptamer dendrimer nanoconjugates for enormous therapeutic effect via superior intratumor penetration over antibody counterparts.

Antibody-coated nanoparticles have been reported to have the extremely low delivery efficiency in solid tumors in preclinical trials. Though aptamers were considered to be superior over antibodies in cancer theranostics, whether PEGylated aptamer nanoparticles are better than antibody nanoparticles in improving delivery specificity and penetration efficiency of chemotherapeutics is still unknown. Here, we conjugate celastrol, a natural product with anti-tumor effect, onto PEGylated EpCAM aptamer or antibody dendrimers to obtain two nanoconjugates, and for the first time, conduct a comprehensive study to compare their performance in delivery specificity, intratumoral penetration ability and therapeutic outcomes.

CAR cell design strategies in solid tumors.

In addition to chimeric antigen receptor (CAR)-αβ T-cell therapy, CAR-NK, CAR-NKT, CAR-M and CAR-γδ T-cell therapy have gradually been applied to the treatment of solid tumors. Compared to hematological tumors, solid tumors have the characteristics of strong tumor heterogeneity, limited target antigen selection, and low T-cell infiltration to build immunosuppressive tumor microenvironment. These features would present great obstacles to CAR cell therapy.

Hybrid Biomimetic Nanovesicles to Drive High Lung Biodistribution and Prevent Cytokine Storm for ARDS Treatment.

Acute respiratory distress syndrome (ARDS) has been a life threat for patients in ICUs. Vast efforts have been devoted, while no medication has proved viable, which may be ascribed to inadequate drug delivery to damaged tissues and insufficient control of lung inflammation. Given the anti-inflammatory role of M2-type macrophages, M2 macrophage-derived nanovesicles and lung-targeting liposomes are cofused to fabricate hybrid liposomes-nanovesicles (LNVs).

Cell-Derived Biogenetic Gold Nanoparticles for Sensitizing Radiotherapy and Boosting Immune Response against Cancer.

The biosynthesis of nanomedicine has gained enormous attention and exhibited promising prospects, while the underlying mechanism and advantage remain not fully understood. Here, a cell-reactor based on tumor cells is developed to obtain biogenetic gold nanoparticles (Au@MC38) for sensitizing radiotherapy and boosting immune responses. It demonstrates that the intracellular biomineralization and exocytosis process of Au@MC38 can be regulated by the cellular metabolites level and other factors, such as glutathione and reactive oxygen species (ROS), autophagy, and UV irradiation.

Interplay between transforming growth factor-β and Nur77 in dual regulations of inhibitor of differentiation 1 for colonic tumorigenesis.

The paradoxical roles of transforming growth factor-β (TGFβ) signaling and nuclear receptor Nur77 in colon cancer development are known but the underlying mechanisms remain obscure. Inhibitor of differentiation 1 (ID1) is a target gene of TGFβ and a key promoter for colon cancer progression. Here, we show that Nur77 enhances TGFβ/Smad3-induced ID1 mRNA expression through hindering Smurf2-mediated Smad3 mono-ubiquitylation, resulting in ID1 upregulation.

Macroporous organosilicon nanocomposites co-deliver Bcl2-converting peptide and chemotherapeutic agent for synergistic treatment against multidrug resistant cancer.

Therapeutic biomacromolecules are confronted with in vivo challenges of low bio-stability and poor tumor tissue-penetration. Herein, we report for the first time, our development and characterization of a hybrid nanocomposite for delivering a Bcl-2-converting peptide (NuBCP9, N9 hereafter) and testing its efficacy alone or together with doxorubicin (DOX). The hybrid nanocomposite is composed of the internal large pore sized-mesoporous silica nanoparticles (MSNs) and the external highly-branched polyamidoamine (PAMAM) dendrimers, into which N9 peptide and DOX were encapsulated for the different sub-cellular delivery to treat drug-resistant cancer.

Macroporous silica nanoparticles for delivering Bcl2-function converting peptide to treat multidrug resistant-cancer cells.

The abundance of B cell lymphoma gene 2 (Bcl-2) is closely correlated with the resistance of cancer cells to chemotherapeutic agents, and a peptide derived from orphan nuclear receptor Nur77 can convert Bcl-2 from a protector to a killer of cancer cells. However, successful application of the Bcl-2-converting peptide to treat drug-resistant cancer cells depends on an efficient delivery carrier. Mesoporous silica nanoparticles (MSNs) have been extensively studied as promising candidates for small molecule drug delivery.

RGD-decorated redox-responsive d-α-tocopherol polyethylene glycol succinate-poly(lactide) nanoparticles for targeted drug delivery.

Developing multifunctional nanoparticles (NPs) to improve therapeutic efficacy is highly desirable in cancer therapy. In an attempt to respond to such a challenge, a novel copolymer, d-α-tocopherol polyethylene glycol succinate-SS-poly(lactide) (TPGS-SS-PLA) with a disulfide linkage between the TPGS and PLA units, was synthesized for paclitaxel (PTX) delivery. PTX-loaded NPs were fabricated using a nanoprecipitation method to form a particle size of ∼130 nm with good in vitro stability, which can be disassociated under intracellular reductive conditions to release PTX rapidly.