Mechanisms and therapeutic targets of ferroptosis: Implications for nanomedicine design.

Ferroptosis is a nonapoptotic form of cell death and differs considerably from the well-known forms of cell death in terms of cell morphology, genetics, and biochemistry. The three primary pathways for cell ferroptosis are system Xc-/glutathione peroxidase 4 (GPX4), lipid metabolism, and ferric metabolism. Since the discovery of ferroptosis, mounting evidence has revealed its critical regulatory role in several diseases, especially as a novel potential target for cancer therapy, thereby attracting increasing attention in the fields of tumor biology and anti-tumor therapy. Accordingly, broad prospects exist for identifying ferroptosis as a potential therapeutic target. In this review, we aimed to systematically summarize the activation and defense mechanisms of ferroptosis, highlight the therapeutic targets, and discuss the design of nanomedicines for ferroptosis regulation. In addition, we opted to present the advantages and disadvantages of current ferroptosis research and provide an optimistic vision of future directions in related fields. Overall, we aim to provide new ideas for further ferroptosis research and inspire new strategies for disease diagnosis and treatment.

Radiofrequency-responsive black phosphorus nanogel crosslinked with cisplatin for precise synergy in multi-modal tumor therapies.

Radiofrequency-responsive nanoparticles (RFNPs) have drawn increasingly attentions as RF energy absorbing antenna to enhance antitumor efficacy of radiofrequency ablation (RFA). However, it remains a huge challenge for inorganic RFNPs to precisely synergize RFA with other antitumor modes in a clinically acceptable way on bio-safety and bio-compatibility. In this work, RF-responsive black phosphorus (BP) nanogel (BP-Pt@PNA) was successfully fabricated by crosslinking coordination of cisplatin with BP and temperature sensitive polymer PNA. BP-Pt@PNA exhibited strong RF-heating effect and RF-induced pulsatile release of cisplatin. Under RF irradiation, BP-Pt@PNA exhibited cytotoxic enhancement on 4T1 cells. By the synergistic effect of BP and cisplatin, BP-Pt@PNA achieved RF-stimulated systemic immune effect, thus induced enhance suppression on tumor growth and metastasis. Moreover, BP-Pt@PNA realized long-term drug retention in tumor and favorable embolization to tumor-feeding arteries. With high drug loading capacity and favorable bio-safety and bio-degradability, BP-Pt@PNA is expected as an ideal RFNP for precisely synergizing RFA with other antitumor modes in clinical application.

Structure-activity relationship study of 1,6-naphthyridinone derivatives as selective type II AXL inhibitors with potent antitumor efficacy.

The role of AXL in various oncogenic processes has made it an attractive target for cancer therapy. Currently, kinase selectivity profiles, especially circumventing MET inhibition, remain a scientific issue of great interest in the discovery of selective type II AXL inhibitors. Starting from a dual MET/AXL-targeted lead structure from our previous work, we optimized a 1,6-naphthyridinone series using molecular modeling-assisted compound design to improve AXL potency and selectivity over MET, resulting in the potent and selective type II AXL-targeted compound 25c. This showed excellent AXL inhibitory activity (IC50 = 1.1 nM) and 343-fold selectivity over the highly homologous kinase MET in biochemical assays. Moreover, compound 25c significantly inhibited AXL-driven cell proliferation, dose-dependently suppressed 4T1 cell migration and invasion, and induced apoptosis. Compound 25c also showed noticeable antitumor efficacy in a BaF3/TEL-AXL xenograft model at well-tolerated doses. Overall, this study presented a potent and selective type II AXL-targeted lead compound for further drug discovery.

Characterization of Chitosan-Gallic Acid Graft Copolymer for Periodontal Dressing Hydrogel Application.

The postoperative periodontal wound is in a complex physiological environment; the bacteria accumulation, the saliva stimulation, and the food residues retention will aggravate the wound deterioration. Commercial periodontal dressings have been widely used for postoperative periodontal treatment, and there still exists some problems, such as poor biocompatibility, weak adhesion, insufficient antibacterial, and anti-inflammatory properties. In this study, a chitosan-gallic acid graft copolymer (CS-GA) is synthesized as a potential periodontal dressing hydrogel. CS-GA possesses high swelling rate, adjustable degradability, self-healing ability, biocompatibility, strong adhesion ability, high mechanical properties and toughness. Furthermore, CS-GA has good scavenging ability for ·OH, O2 - , and 1 O2. And CS-GA has good inhibition effect on different bacterial through bacterial membranes damage. CS-GA can stop bleeding in a short time and adsorb erythrocytes to form physical blood clots to enhance the hemostatic performance. In addition, CS-GA can reduce inflammatory factors expressions, increase collagen fibers deposition, and neovascularization to promote wounds healing, which makes it as a potential periodontal dressing for postoperative tissue restoration.

Radiofrequency-Activated Pyroptosis of Bi-Valent Gold Nanocluster for Cancer Immunotherapy.

Pyroptosis is gasdermin-mediated programmed necrosis that exhibits promising potential application in cancer immunotherapy, and the main challenge lies in how to provoke specific pyroptosis of tumor cells. Here, biGC@PNA with a precisely stoichiometric ratio of Au(I) ion/Au(0) atom induced pyroptosis of tumor cells by its radiofrequency (RF)-heating effect. An in vitro/in vivo assay on 4T1 tumor cells indicates RF-activated pyroptosis of tumor cells elicits a robust ICD effect, enhancing the synergistic antitumor efficacy of biGC@PNA with decitabine, significantly suppressing tumor metastasis and relapse by provoking systemic antitumor immune responses. Utilizing RF-activated pyroptotic immune responses, biGC@PNA efficiently enhances the antitumor efficacy of αPD-1 immunotherapy under RF irradiation and provides a promising strategy for improving cancer immunotherapy by the noninvasive RF field with high clinical transformation potential.

Engineering Ferroptosis Inhibitors as Inhalable Nanomedicines for the Highly Efficient Treatment of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) refers to chronic progressive fibrotic interstitial pneumonia. It is called a "tumor-like disease" and cannot be cured using existing clinical drugs. Therefore, new treatment options are urgently needed. Studies have proven that ferroptosis is closely related to the development of IPF, and ferroptosis inhibitors can slow down the occurrence of IPF by chelating iron or reducing lipid peroxidation. For example, the ferroptosis inhibitor deferoxamine (DFO) was used to treat a mouse model of pulmonary fibrosis, and DFO successfully reversed the IPF phenotype and increased the survival rate of mice from 50% to 90%. Given this, we perceive that the treatment of IPF by delivering ferroptosis inhibitors is a promising option. However, the delivery of ferroptosis inhibitors faces two bottlenecks: low solubility and targeting. For one thing, we consider preparing ferroptosis inhibitors into nanomedicines to improve solubility. For another thing, we propose to deliver nanomedicines through pulmonary drug-delivery system (PDDS) to improve targeting. Compared with oral or injection administration, PDDS can achieve better delivery and accumulation in the lung, while reducing the systemic exposure of the drug, and is an efficient and safe drug-delivery method. In this paper, three possible nanomedicines for PDDS and the preparation methods thereof are proposed to deliver ferroptosis inhibitors for the treatment of IPF. Proper administration devices and challenges in future applications are also discussed. In general, this perspective proposes a promising strategy for the treatment of IPF based on inhalable nanomedicines carrying ferroptosis inhibitors, which can inspire new ideas in the field of drug development and therapy of IPF.

NIR-triggered ligand-presenting nanocarriers for enhancing synergistic photothermal-chemotherapy.

Surface PEGylation of nanomedicine is effective for prolonging blood circulation time and facilitating the EPR effect, whereas the hydrophilic stealth surface inhibits effective cellular uptake and hinders active targeting. To address the dilemma, herein, a NIR light-triggered dePEGylation/ligand-presenting strategy based on thermal decomposition of azo bonds is developed, whereby Dox/Pz-IR nanoparticle is self-assembled from thermo-labile azo molecule-linked long PEG chain polymer (Pz-IR), cRGD-conjugated IR783 with short PEG chains (rP-IR) and doxorubicin. The long PEG chains could mask cRGD peptides in the blood circulation, preventing serum degradation and nonspecific interaction with normal cells. Once exposed to NIR laser, the PEG corona is stripped off owing to the rupture of azo bonds through the photothermal effect of IR783, and the masked cRGD peptides are exposed, which remarkably enhances cellular uptake by tumor cells and improves tumor accumulation. Dox/Pz-IR achieves the optimal synergy of photothermal-chemotherapy at mild temperature through progressive tumor accumulation, precisely regulated photothermal effect and NIR-PTT induced pulsated drug release. The strategy of NIR photo-driven dePEGylation/targeting offers a new approach to overcoming the "PEG dilemma", and provides a noval avenue for programmed tumor-targeted drug delivery.

Mapping the intersection of nanotechnology and SARS-CoV-2/COVID-19: A bibliometric analysis.

Background: Coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has imposed great medical and economic burdens on human society, and nanotechnology is a promising technique for managing the ongoing COVID-19 pandemic. To drive further studies on anti-COVID-19 nanotechnology, this paper provides an analysis, from a bibliometric perspective, of the intersection of nanotechnology and SARS-CoV-2/COVID-19. Methods: We analyzed the 2585 publications on nanotechnology and SARS-CoV-2/COVID-19 included in the Web of Science Core Collection from January 2019 to March 2022 to determine the bibliometric landscape. The basic bibliometric characteristics are summarized in this article. Results: Our bibliometric analysis revealed that the intersection between nanotechnology and SARS-CoV-2/COVID-19 is a cutting-edge field in the science community and that the related studies were multidisciplinary in nature. Studies on the structural basis of SARS-CoV-2, SARS-CoV-2 detection assays, and mRNA vaccines against COVID-19 provided the development foundation for this field. Conclusions: The current research focuses are the development of nanomaterial-based vaccines and SARS-CoV-2 detection methods, and the design of nanomedicines carrying SARS-CoV-2 inhibitors is a relatively burgeoning frontier. In summary, this bibliometric analysis of the intersection of nanotechnology and SARS-CoV-2/COVID-19 highlights the current research focuses of this field to inspire future studies on anti-COVID-19 nanotechnologies.

Explicating the publication paradigm by bibliometric approaches: A case of interplay between nanoscience and ferroptosis.

Background: Ferroptosis has been widely investigated as an emerging drug target, while its combination with nanoscience provides bourgeoning application prospects. The development of ferroptosis regulating nanomedicines have attracted worldwide attentions in recent years. It would be meaningful to describe the relevant publication paradigm. Methods: Herein, a bibliometric analysis was performed using the database of Web of Science Core Collection to clarify the publication paradigm. The development of related publications in the last 6 years was described, and the revolutionary trends were figured out. Ultimately, the possible future exploration directions were proposed. Results: The bibliometric analysis of 327 documents of interest indicated that the main research focus was in multiple fields including Materials science, Science & technology, Chemistry, and Pharmacology & pharmacy. With widely cooperation and strong funding, the researchers from Chinese organizations contributed most of publications, followed with United States and Australia. Cocitation analysis revealed that several original papers reported the key molecular mechanisms of ferroptosis were considered as the foundation for subsequent studies, and some nanomedicines-related documents were taken as examples and discussed. Mining results showed that the mechanism evaluation of ferroptosis regulation therapy for cancer treatment was the hotspot. Then, several possible future explorations of ferroptosis-related nanoscience were presented and discussed. Conclusions: The bibliometric profile of nanoscience-ferroptosis research was analyzed in detail. We believe that the bibliometric analysis could act as a robust method for explicating the publication paradigm as a certain field.