A platelet‐membrane‐coated biomimetic nanocarrier, which can sequentially target the bone microenvironment and myeloma cells to enhance the drug availability at the myeloma site and decrease ...off‐target effects, is developed for inhibiting multiple myeloma growth and simultaneously eradicating thrombus complication.
Exploring the response of malignant cells to intracellular metabolic stress is critical for understanding pathologic processes and developing anticancer therapies. Herein, we developed ...ferritin-targeting proteolysis targeting chimeras (PROTACs) to establish the iron excess stress inside cancer cells and investigated subsequent cellular behaviors. We conjugated oleic acid that binds to the ferritin dimer to the ligand of von Hippel–Lindau (VHL) E3 ligase through an alkyl linker. The screened chimera, DeFer-2, degraded ferritin and then rapidly elevated the free iron content, thereby initiating the caspase 3-GSDME-mediated pyroptosis in cancer cells rather than typical ferroptosis that is always associated with iron ion overload. According to its structural and physicochemical characteristics, DeFer-2 was loaded into a tailored albumin-based nano-formulation, which substantially inhibited tumor growth and prolonged the survival time of mice bearing B16F10 subcutaneous tumors with negligible adverse effects. This study developed a ferritin-targeting PROTAC for iron overload stress, revealed iron metabolic dysregulation-mediated pyroptosis, and provided a PROTAC-based pyroptosis inducer for anticancer treatment.
The regeneration of cartilage, an aneural and avascular tissue, is often compromised by its lack of innate abilities to mount a sufficient healing response. Kartogenin (KGN), a small molecular ...compound, can induce bone marrow-derived mesenchymal stem cells (BMSCs) into chondrocytes. The previous in vitro study showed that kartogenin also had a chondrogenesis effect on synovium derived mesenchymal stem cells (SMSCs). Herein, we present the effect of an ultraviolet-reactive, rapidly cross-linkable scaffold integrated with kartogenin-loaded nanoparticles using an innovational one-step technology. In vivo studies showed its potential role for cell homing, especially for recruiting the host’s endogenous cells, including BMSCs and SMSCs, without cell transplantation. Of note, the regenerated tissues were close to the natural hyaline cartilage based on the histological tests, specific markers analysis, and biomechanical tests. This innovative KGN release system makes the chondrogenesis efficient and persistent.
A “relay drug delivery” system based on two distinct modules, which is composed of a signal transmission nanocarrier A (NCA) that can specifically induce tumor blood vessel inflammation generation ...and an execution biomimetic nanocarrier B (NCB) that can accumulate at the tumor site by receiving the broadcasting signals generated by NCA, is developed for amplifying active tumor targeting signal and enhancing antitumor therapy.
Protein therapy has been considered the most direct and safe approach to treat cancer. Targeting delivery of extracellularly active protein without internalization barriers, such as membrane ...permeation and endosome escape, is efficient and holds vast promise for anticancer treatment. Herein, we describe a “transformable” core–shell based nanocarrier (designated CS-NG), which can enzymatically assemble into microsized extracellular depots at the tumor site with assistance of hyaluronidase (HAase), an overexpressed enzyme at the tumor microenvironment. Equipped with an acid-degradable modality, the resulting CS-NG can substantially release combinational anticancer drugstumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL) and antiangiogenic cilengitide toward the membrane of cancer cells and endothelial cells at the acidic tumor microenvironment, respectively. Enhanced cytotoxicity on MDA-MB-231 cells and improved antitumor efficacy were observed using CS-NG, which was attributed to the inhibition of cellular internalization and prolonged retention time in vivo.
Inflammatory bowel diseases (IBDs) are often associated with elevated levels of reactive oxygen species (ROS) and highly dysregulated gut microbiota. In this study, we synthesized a polymer of ...hyaluronic acid-poly(propylene sulfide) (HA-PPS) and developed ROS-scavenging nanoparticles (HPN) that could effectively scavenge ROS. To achieve colon tissue targeting effects, the HPN nanoparticles were conjugated to the surface of modified probiotic
Nissle 1917 (EcN). To enhance the bacteriotherapy of EcN, we encapsulated EcN cells with a poly-norepinephrine (NE) layer that can protect EcN against environmental assaults to improve the viability of EcN in oral delivery and prolong the retention time of EcN in the intestine due to its strong mucoadhesive capability. In the dextran sulfate sodium-induced mouse colitis models, HPN-NE-EcN showed substantially enhanced prophylactic and therapeutic efficacy. Furthermore, the abundance and diversity of gut microbiota were increased after treatment with HPN-NE-EcN, contributing to the alleviation of IBDs.
Abstract Chimeric antigen receptor (CAR) T cell therapy is a form of adoptive cell therapy that has revolutionized the field of cancer immunotherapy. Owing to the unprecedented efficacy seen in the ...treatment of blood cancers, the FDA has now approved multiple CAR T cell products for the treatment of various hematologic malignancies. Despite the clinical success seen in hematologic malignancies, CAR T cell therapies have demonstrated only modest efficacy in the treatment of solid tumors. Thus, great efforts are underway to increase the treatment efficacy in solid tumors and further enhance the treatment of hematologic malignancies. However, irrespective of advancements in efficacy, there are still unmet needs for patients receiving CAR T cell therapies. CAR T cell therapies carry significant risks of potentially fatal toxicities, and few of these toxicities were predicted in the animal models used to advance these therapies to the clinic. Therefore, significant advancements are needed to help reduce the incidence and severity of these toxicities to ultimately enhance patient safety and quality of life. This review will provide a brief overview of some of the major toxicities associated with CAR T cell therapies and will discuss the various engineering strategies used to mitigate such toxicities in preclinical models and clinical studies.
Melanin is capable of transforming 99.9% of the absorbed sunlight energy into heat, reducing the risk of skin cancer. We here develop a melanin-mediated cancer immunotherapy strategy through a ...transdermal microneedle patch. B16F10 whole tumor lysate containing melanin is loaded into polymeric microneedles that allow sustained release of the lysate upon insertion into the skin. In combination with the near-infrared light irradiation, melanin in the patch mediates the generation of heat, which further promotes tumor-antigen uptake by dendritic cells, and leads to enhanced antitumor vaccination. We found that the spatiotemporal photoresponsive immunotherapy increases infiltration of polarized T cells and local cytokine release. These immunological effects increase the survival of mice after tumor challenge and elicited antitumor effects toward established primary tumor and distant tumor. Collectively, melanin generates local heat, boosts T cell activities by transdermal vaccines, and promotes antitumor immune responses.
Immunotherapy has achieved revolutionary success in clinics, but it remains challenging for treating hepatocellular carcinoma (HCC) characterized by high vascularization. Here, it is reported that ...metal–organic framework‐801 (MOF‐801) can be employed as a stimulator of interferon genes (STING) through Toll‐like receptor 4 (TLR4) not just as a drug delivery carrier. Notably, cytosine–phosphate–guanine oligodeoxynucleotides (CpG ODNs) and 5, 6‐dimethylxanthenone‐4‐acetic acid (DMXAA) STING agonist with vascular disrupting function coordinates with MOF‐801 to self‐assemble into a nanoparticle (MOF‐CpG‐DMXAA) that effectively delivers CpG ODNs and DMXAA to cells for synergistically improving the tumor microenvironment by reprogramming tumor‐associated macrophages (TAMs), promoting dendritic cells (DCs) maturation, as well as destroying tumor blood vessels. In HCC‐bearing mouse models, it is demonstrated that MOF‐CpG‐DMXAA triggers systemic immune activation and stimulates robust tumoricidal immunity, resulting in a superior immunotherapeutic efficiency in orthotopic and recurrent HCC.
A multifunctional therapeutic immune‐nanomedicine, MOF‐CpG‐DMXAA, effectively delivers cytosine–phosphate–guanine oligodeoxynucleotides (CpG ODNs) and 5,6‐dimethylxanthenone‐4‐acetic acid (DMXAA) to improve the miserable immune response by reprogramming tumor‐associated macrophages (TAMs), promoting dendritic cells (DCs) maturation and inhibiting angiogenesis, achieving synergistically immunotherapy. MOF‐CpG‐DMXAA significantly enhances stimulator of interferon genes (STING) activation, reverses the immunosuppression state and stimulates robust tumoricidal immunity, exhibiting a synergistic efficiency to eradicate hepatocellular carcinoma.
Cell-based therapy holds great potential to address unmet medical needs and revolutionize the healthcare industry, as demonstrated by several therapeutics such as CAR-T cell therapy and stem cell ...transplantation that have achieved great success clinically. Nevertheless, natural cells are often restricted by their unsatisfactory
in vivo
trafficking and lack of therapeutic payloads. Chemical engineering offers a cost-effective, easy-to-implement engineering tool that allows for strengthening the inherent favorable features of cells and confers them new functionalities. Moreover, in accordance with the trend of precision medicine, leveraging chemical engineering tools to tailor cells to accommodate patients individual needs has become important for the development of cell-based treatment modalities. This review presents a comprehensive summary of the currently available chemically engineered tools, introduces their application in advanced diagnosis and precision therapy, and discusses the current challenges and future opportunities.
This review summarizes chemical tools for cell engineering, introduces their wide application in diagnosis and therapy, and discusses the challenges and opportunities in precision medicine.
PDF
