Small-Molecule Ferritin Degrader as a Pyroptosis Inducer.

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.

Unfolded Protein Corona Surrounding Nanotubes Influence the Innate and Adaptive Immune System.

The plasma proteins around nanoparticles (NPs) form an outer protein corona, significantly influencing the subsequent immune response. However, it was uncertain whether the protein corona around NPs influences immune response. This study clarified that the immune response mediated by the protein corona is greatly dependent on the type of plasma proteins surrounding the NPs. Structural changes in the unfolded protein corona elevated reactive oxygen species (ROS) levels and induced major proinflammatory cytokine release in both murine and human macrophage cell lines. In contrast, negligible structural changes in the protein corona provoke neither ROS production nor proinflammatory cytokine release. Furthermore, in vivo analysis confirms that a stimulated immune response by an unfolded protein corona triggers selective activation of innate and adaptive immunity in the spleen. Specifically, neutrophils, natural killer cells, and CD8+ T cells are overpopulated by unfolded protein corona structures surrounding nanotubes, whereas innate and adaptive immunologic responses are not triggered by a normal protein corona. In conclusion, highly unfolded protein corona structures are strongly correlated with subsequent activation of proinflammatory cytokines and innate immune responses; thus, the protein corona can be used in immune-enhancing therapy.

Potential Therapeutic Usage of Nanomedicine for Glaucoma Treatment.

Glaucoma is a group of diseases characterized by progressive degeneration of retinal ganglion cells, leading to irreversible blindness. Currently, intraocular pressure reduction is the only established treatment available for glaucoma. With this treatment, the progression of the disease can only be delayed and there is no recovery. In addition, the commercially available eye drops have the disadvantage of low compliance and short therapeutic time, while glaucoma surgery always has the risk of failure due to wound fibrosis. Nanotechnology can overcome the limitations of the current treatment through the encapsulation and conjugation of drugs used for lowering intraocular pressure and antifibrotic agents using biodegradable or biocompatible nanoparticles for the sustained release of the drugs to protect the damaged ocular cells. Furthermore, using nanotechnology, treatment can be administered in various forms, including eye drops, contact lens, and ocular inserts, according to the convenience of the patients. Despite the promising results of delaying the progression of glaucoma, the regeneration of damaged ocular cells, including trabecular meshwork and retinal ganglion cells, is another critical hurdle to overcome. Bone marrow-derived mesenchymal stem cells and Müller glia cells can secrete neurogenic factors that trigger the regeneration of associated cells, including trabecular meshwork and retinal ganglion cells. In conclusion, this review highlights the potential therapeutic applications of nanotechnology- and stem cell-based methods that can be employed for the protection and regeneration of ocular cells.

Triamcinolone-Gold Nanoparticles Repolarize Synoviocytes and Macrophages in an Inflamed Synovium.

Understanding the crosstalk between synoviocytes and macrophages is very important for the development of strategies to regulate inflammatory responses in an inflamed synovium. Simultaneous regulation of the pro- and anti-inflammatory responses of synoviocytes and macrophages (repolarization) is critical for the treatment of arthritis. Thus, the immune regulatory functions of an ideal nanodrug should not only decrease the pro-inflammatory response but also effectively increase the anti-inflammatory response. In this study, crosstalk between synoviocytes and macrophages was found to be significantly involved in the activation and deactivation of inflammatory responses in the synovium. Interestingly, a developed triamcinolone-gold nanoparticle (Triam-AuNP) complex both decreased the pro-inflammatory responses and increased the anti-inflammatory responses of fibroblast-like synoviocytes (FLSs) and macrophages via repolarization of macrophages from the M1 to the M2 phenotype. In contrast, triamcinolone alone only decreased the pro-inflammatory responses of FLSs and macrophages without upregulating their anti-inflammatory responses. In vitro (human), ex vivo (human), and in vivo (mouse) analyses clearly indicated that Triam-AuNPs effectively regulated the expression of both pro- and anti-inflammatory cytokines in FLSs and effectively repolarized activity of macrophages in the inflamed synovium. Furthermore, Triam-AuNPs significantly promoted cartilage regeneration, whereas triamcinolone alone did not induce either FLS anti-inflammatory activity or macrophage repolarization.

Apoptotic lysosomal proton sponge effect in tumor tissue by cationic gold nanorods.

Despite the lysosomal "proton sponge hypothesis" being considered to be an additional factor for stimulating the cellular toxicity of nanoparticle-based drug delivery systems, a clear relationship between the massive influx of calcium ions and the proton sponge effect, both of which are associated with cancer cell apoptosis, has still not been elucidated. Cetrimonium bromide (CTAB: cationic quaternary amino group based) gold nanorods possessed a more effective electric surface charge for inducing the lysosomal proton sponge effect than anionic gold nanoparticles. In this aspect, identifying released cytoplasmic Cl-, arising from the ruptured lysosomal compartment, in the cytoplasm is critical for supporting the "proton sponge hypothesis". This study clarified that the burst release of Cl-, as a result of lysosomal swelling by CTAB gold nanorods, stimulates the transient receptor potential channels melastatin 2 (TRPM2) channels, and subsequently induces a massive Ca2+ influx, which independently increases apoptosis of cancer cells. Although the previous concept of elevated cancer apoptosis acting through the proton sponge effect is unclear, this study supports the evidence that a massive Ca2+ influx mediated in response to a burst release of Cl- significantly influenced cytotoxicity of cancer cells in tumor tissues.

Mesenchymal stem cell therapy assisted by nanotechnology: a possible combinational treatment for brain tumor and central nerve regeneration.

Mesenchymal stem cells (MSCs) intrinsically possess unique features that not only help in their migration towards the tumor-rich environment but they also secrete versatile types of secretomes to induce nerve regeneration and analgesic effects at inflammatory sites. As a matter of course, engineering MSCs to enhance their intrinsic abilities is growing in interest in the oncology and regenerative field. However, the concern of possible tumorigenesis of genetically modified MSCs prompted the development of non-viral transfected MSCs armed with nanotechnology for more effective cancer and regenerative treatment. Despite the fact that a large number of successful studies have expanded our current knowledge in tumor-specific targeting, targeting damaged brain site remains enigmatic due to the presence of a blood-brain barrier (BBB). A BBB is a barrier that separates blood from brain, but MSCs with intrinsic features of transmigration across the BBB can efficiently deliver desired drugs to target sites. Importantly, MSCs, when mediated by nanoparticles, can further enhance tumor tropism and can regenerate the damaged neurons in the central nervous system through the promotion of axon growth. This review highlights the homing and nerve regenerative abilities of MSCs in order to provide a better understanding of potential cell therapeutic applications of non-genetically engineered MSCs with the aid of nanotechnology.

Clinical Application of Bone Morphogenetic Protein-2 Microcarriers Fabricated by the Cryopolymerization of Gelatin Methacrylate for the Treatment of Radial Fracture in Two Dogs.

Bone morphogenetic protein-2 (BMP-2) effectively induces bone healing. However, the efficacy of BMP-2 relies heavily on its delivery vehicle because of its short half-life. We utilized a microcarrier fabricated by the cryopolymerization of gelatin methacrylate (cryoGelMA) infused with bone morphogenetic protein-2 (cryoGelMA-BMP-2) for the sustained and localized release of growth factors. Two dogs with radius and ulnar fractures were treated with implanted cryoGelMA-BMP-2 to accelerate bone healing. The cases were followed up for 6 months and 2 months after surgery, respectively. Distinctive healing processes were observed. The operated limb regained its premorbid function, the fracture line disappeared, and the gait was functionally stable. Implantation of cryoGelMA-BMP-2 resulted in the successful healing of bone fractures.