Background: Ocular drug delivery is hindered by the eye’s complex anatomy and multiple physiological barriers. Because of their biocompatibility, biodegradability, and capacity to prolong drug retention, hydrogels have emerged as promising platforms for ocular drug delivery. This study provides a bibliometric and visual analysis of research on hydrogel-based ocular drug delivery from 1991 to 25 August 2025. Methods: Publications were retrieved from the Web of Science Core Collection and screened for relevance. CiteSpace, VOSviewer, and the Bibliometrix R package were used to analyze annual publication trends, contributions and collaborations among countries, institutions, and authors, core journals, and evolving research themes. Results: A total of 1354 publications (991 articles and 363 reviews) were included. Annual output increased markedly after 2007–2008, reflecting rapid growth in this field. China and the USA were the leading contributors, and the University of Florida was the most productive institution. Keyword co-occurrence, clustering, and burst analyses identified in situ hydrogels, tissue engineering applications, and anti-VEGF delivery as major research hotspots. Conclusions: This study maps the growth and diversification of hydrogel-based ocular drug delivery research, revealing a shift toward disease- and segment-specific applications, with controlled-release, stimuli-responsive systems, injectable hydrogels, and anti-VEGF as emerging research priorities.

While lineage plasticity is a well-established driver of therapy resistance in prostate cancer, the role of tumor-infiltrating immune cells in mediating phenotype switching remains poorly understood. Here, we employed single-cell multi-omics to systematically characterize immune infiltration dynamics, transcriptional reprogramming, and intercellular communication networks during prostate cancer progression. Our analysis revealed that granulin (GRN)-expressing macrophages orchestrate the transition from adenocarcinoma (Adeno) to a therapy-resistant multilineage state exhibiting vimentin (VIM)+ mesenchymal and stem-like features through GRN/ tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) interaction and the subsequent activation of the nuclear factor kappa-B (NF-κB) pathway. Intriguingly, these plastic tumor subclones reciprocally enhanced GRN expression in macrophages via colony stimulating factor 1 (CSF1) and CSF1 receptor (CSF1R) receptor-ligand axis, establishing a feedforward signaling loop that sustains lineage plasticity. Functional validation demonstrated GRN's critical role in driving epithelial-mesenchymal transition in vitro and conferring resistance to enzalutamide (ENZ) in patient-derived organoids. Therapeutic intervention studies in transgenic Adeno of the mouse prostate (TRAMP) models showed that CSF1R inhibition disrupted this vicious cycle, reducing GRN  + macrophages and suppressing multilineage subclone emergence. Spatial mapping revealed direct physical interactions between VIM  + tumor cells and GRN  + macrophages, while single-cell proteomics in castration-resistant patients confirmed the clinical relevance of this axis. Furthermore, we identified three novel stromal populations [decorin (DCN)+ endothelial cells, C-C motif chemokine ligand 7 (CCL7)+ fibroblasts, and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1)+ neutrophils associated with disease relapse. These findings illuminate the tumor-immune crosstalk underlying treatment resistance and unveil promising therapeutic targets for overcoming lineage plasticity-driven resistance in advanced prostate cancer.

Mutation-intolerant genes (MIGs), which are constrained in tumors yet variable in normal tissues, are critical for cancer survival. Herein, we developed miDriver, a computational framework using pancancer-normal mutation contrasts to identify 1,020 MIGs across 8,096 tumors of 13 cancer types. Strikingly, MIGs are highly associated with synthetic lethality, cell-cycle progression, and clinical outcome. CRISPR screening reveals MIGs, especially CHEK1, as cancer-specific vulnerabilities, whose suppression impairs tumor proliferation and migration. Single-cell transcriptomics reveals a CHEK1-high subpopulation exhibiting stem-like and immune-suppressed features, linking tumor-intrinsic fitness to microenvironment remodeling. Multiplexed immunofluorescence revealed that CHEK1 and MIF are co-expressed in tumor cells, and CHEK1-high tumor cells exhibit closer spatial proximity to M2-like macrophages. Mechanistically, CHEK1 promotes p53 phosphorylation to upregulate MIF expression and secretion, thereby driving M2-like macrophage polarization via the MIF-CD74 axis. In vivo, targeting the CHEK1-MIF axis (particularly CHEK1) broadly reverses immunosuppression. Clinically, higher tumor CHEK1 levels are associated with poorer response to anti-PD-1 therapy. Exemplified by CHEK1, these findings establish MIGs as dual therapeutic targets capable of simultaneously disrupting tumor-intrinsic fitness and remodeling the immunosuppressive niche. This work proposes a novel paradigm for selectively targeting MIGs to eliminate aggressive tumor subclones while minimizing toxicity to normal cells.

Nonsmall cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality, with MYC oncogene overexpression driving tumor progression and immunosuppression. MYC has been deemed "undruggable" for a long period, and the impact of its silencing on the tumor associated macrophage polarization and circadian rhythm remains unexplored. Here, we developed a lipid nanoparticle (siMYC@Dmix) composed of cytidinyl lipid (DNCA), gemini-like cationic lipid (CLD), and DSPE-PEG2000 for efficient MYC siRNA delivery. In vitro, siMYC@Dmix showed robust cellular uptake, lysosomal escape, and ∼77% MYC mRNA silencing in Lewis Lung Carcinoma (LLC) cells. In vivo, siMYC@Dmix treatment significantly inhibited tumor growth in C57BL/6J mice and induced a profound remodeling of the tumor immune microenvironment. This was characterized by a shift in macrophage polarization toward the M1 phenotype, increased infiltration and cytotoxic function of CD8+ T cells, enhanced natural killer (NK) cell activity, and maturation of dendritic cells (DCs). Crucially, MYC silencing restored the expression of core circadian clock genes. Our findings unveil a promising RNAi-based strategy that concurrently targets MYC-driven tumorigenesis, corrects circadian dysfunction, and reinstates antitumor immunity, presenting a multifaceted therapeutic approach for NSCLC.

Background/Objectives: Observational studies have reported comorbidity between diabetic retinopathy (DR) and physical frailty, but their genetic interplay remains incompletely understood. This study evaluated shared genetic architecture and potential causal relationships between DR severity and frailty-related phenotypes (FRPs). Methods: GWAS summary statistics were analyzed for four DR phenotypes (broad DR, background DR [BDR], severe non-proliferative DR, and proliferative DR [PDR]) and six FRPs, including frailty index (FI), appendicular lean mass, handgrip strength (HGS), and walking pace (UWP). Global and local genetic correlations were estimated using LDSC, HDL, and LAVA. Causality was assessed using bidirectional Mendelian randomization (MR) and latent causal variable (LCV) analyses. Biological mechanisms were investigated using partitioned heritability, cross-trait meta-analysis, Bayesian colocalization, tissue and cell enrichment, prioritization (MAGMA/TWAS), and 3D chromatin annotation. Results: BDR and PDR showed positive genetic correlations with FI and negative correlations with UWP. Local genetic correlation analyses identified 82 significant regions, including signals on chromosome 6. MR supported a directional effect in which genetic liability to DR was associated with higher FI and lower HGS, with no evidence of reverse causation. LCV indicated partial genetic causality within a shared polygenic architecture. Cross-trait meta-analysis and colocalization highlighted the MHC region, prioritizing C2, AIF1, NOTCH4, and EHMT2. Additional non-MHC loci included the BCL2L15 gene cluster and TERF1. Conclusions: DR and frailty share genetic determinants involving neurovascular, metabolic, and immune-inflammatory pathways, supporting an association between DR liability and frailty-related decline. Future longitudinal and functional studies are needed to validate these findings and assess candidate pleiotropic genes.

BACKGROUND AND PURPOSE:EZH2 (enhancer of zeste homologue 2) inhibitors are an emerging class of drugs that target epigenetic regulation. However, their efficacy in solid tumours has been limited, partly due to drug-induced upregulation of fatty acid synthesis. Combining lipid metabolic modulation with EZH2 inhibition may offer a promising strategy to enhance antitumor activity. EXPERIMENTAL APPROACH:We conducted a screen of clinically approved lipid-lowering drugs to identify candidates that could enhance the efficacy of EZH2 inhibitors and found that fenofibrate significantly potentiated the antitumor effects of EZH2 inhibition. Mechanistic studies revealed that this synergistic effect was associated with the degradation of EZH2 protein. To uncover the underlying regulatory pathway, we performed mass spectrometry analysis, which identified the E3 ubiquitin ligase TRIM21 and the deubiquitinase OTUD4 as key mediators of fenofibrate-induced EZH2 degradation. KEY RESULTS:Fenofibrate significantly enhanced the antitumor effects of EZH2 inhibitors in melanoma, independent of its conventional lipid-lowering function. TRIM21 and OTUD4 were identified as critical mediators of this synergistic effect. Fenofibrate disrupted the non-canonical functions of EZH2 by promoting its destabilization, thereby exerting dual effects-inhibiting EZH2 enzymatic activity and accelerating its degradation. Combination therapy with fenofibrate and EZH2 inhibitors resulted in a potent synergistic suppression of tumour growth. CONCLUSIONS AND IMPLICATIONS:Our findings reveal a previously unrecognized role for fenofibrate in augmenting EZH2-targeted therapy. This study provides a novel strategy to improve the efficacy of epigenetic therapies in cancer by combining EZH2 inhibitors with fenofibrate, offering potential clinical benefits for precision oncology.

Tyramide signal amplification (TSA)-induced Opal multiplex immunohistochemistry (mIHC) represents an advanced methodology for the in-situ detection of multiple target proteins. A critical aspect of this technique is the complete removal of primary and secondary antibodies to prevent signal cross-reaction. However, current antibody stripping methods exhibit several limitations, particularly when applied to tissues prone to delamination. Microwave treatment may compromise tissue integrity, additionally, the effectiveness of chemical reagents can be sensitive to variations in temperature, pH, and concentration. This study aims to optimize antibody stripping strategies specifically for use in Opal mIHC protocols, addressing limitations of current methods which particularly for tissues prone to delamination. Evaluation of microwave oven-assisted antibody removal (MO-AR), chemical reagent-based antibody removal (CR-AR), and hybridization oven-based stripping at 50 °C (HO-AR-50) and 98 °C (HO-AR-98) revealed that MO-AR and HO-AR-98 most effectively removed primary and secondary antibodies. In five-color mIHC on mouse kidney sections, both methods yielded strong target-specific signals. However, in brain tissue sections prone to delamination, HO-AR-98 better preserved tissue integrity compared to MO-AR and supported effective multi-target staining. These findings establish a novel thermochemical stripping method compatible with TSA-based Opal mIHC, enhancing its utility in research and clinical diagnostics.

Gliomas are the most common primary brain tumors and characterized by poor prognosis and heavy infiltration of tumor-associated macrophages. Triggering receptor expressed on myeloid cells-2 (TREM2), known to modulate macrophage function, has shown conflicting roles in glioma pathology. In this study, we comprehensively investigated the expression, function, and clinical relevance of TREM2 in gliomas using public datasets, single-cell RNA sequencing (scRNA-seq) analysis, and multiplex immunofluorescence. scRNA-seq identified a distinct subset of microglia-derived macrophages with high TREM2 expression that exhibit a dual phenotype of immunosuppression and enhanced lipid metabolism. These cells show enrichment of genes involved in fatty acid metabolism and lipoprotein clearance, including significant upregulation of apolipoprotein E (APOE), a known TREM2 ligand. Clinically, high TREM2 expression in microglia-derived macrophages correlates with increased tumor grade, recurrence, and shorter overall and disease-free survival. In contrast, APOE expression was correlated with better survival in public datasets, though not significantly in our patient cohort. Our findings suggest that TREM2high microglia-derived macrophages constitute a pro-tumorigenic subpopulation within the glioma microenvironment and may serve as a robust prognostic marker. The interplay between TREM2 and APOE further underscores the immunometabolic complexity of gliomas and points to TREM2 as a promising target for therapeutic intervention.

The role of tumor-infiltrating immune cells in driving phenotype switching remains unclear, despite the well-established association between lineage transition and drug resistance in prostate cancer. This study employed an integrated analysis of single-cell multiomics to investigate the dynamics of immune infiltration, transcriptional programs, and cell-cell communication in prostate cancer. Our results demonstrated that granulin (GRN) positive macrophages facilitated the transition from adenocarcinoma to a multilineage state with mesenchymal and stem-like traits by activating intra-tumoral NF-κB signaling. Subsequently, the multilineage clones induced macrophages to highly express granulin through the secretion of CSF1, forming a positive feedback cell communication loop. Next, we validated the biological function of granulin in mediating epithelial-mesenchymal transition in vitro. Additionally, organoids drug resistance assay demonstrated that granulin drove resistance to androgen receptor (AR)-targeted drug (enzalutamide). Moreover, pharmacologic blockade of the CSF-1/CSF-1R axis in TRAMP mouse models reduced the expression of GRN in macrophages and suppressed the formation of multilineage subclones in prostate malignant cells. Furthermore, multiplex immunofluorescence staining of tumor samples from TRAMP mouse models revealed the VIM lineages were spatially in close contact with macrophages. Meanwhile, Cytometry by Time-Of-Flight (CyTOF) analysis validated our findings at single-cell protein level in patients with castration-resistant prostate cancer. Besides, three distinct tumor-infiltrating subsets associated with disease relapse were identified, including DCN+ endothelial cells, CCL7+ fibroblasts, and IFIT1+ neutrophils. These results offer potential therapeutic targets to address lineage plasticity-driven resistance to AR-targeted therapy. ### Competing Interest Statement The authors have declared no competing interest. National Natural Science Foundation of China, 32470835, 82273131, 82300433

Background and aimsMultiplex immunohistochemistry/immunofluorescence (mIHC/IF), which uses the tyramide signal amplification (TSA) technique, enables sequential staining of multiple targets in formalin-fixed paraffin-embedded (FFPE) samples without worrying about cross-reactivity. This approach has received considerable attention from researchers over the past decades. This article aims to provide a bibliometric analysis of the research progress and perspectives on the application of TSA-based mIHC/IF.MethodsWe collected all the TSA-based mIHC/IF documents published between 2007 and 2023 from the Web of Science Core Collection (WoSCC) database. CiteSpace, VOSviewer and Bibliometrix R Package were used to perform the bibliometrics analysis, including details about annual publications, countries, institutions, authors, journals, and research topics and hotspots.ResultsA total of 873 relevant publications (811 articles and 62 reviews) with a time span of 17 years (2007-2023) were obtained. The number of annual publications started to increase rapidly since 2016. The United States (307, 35.17%) and the People’s Republic of China (297, 34.02%) are the top two listed countries for both the number of articles produced and the citations. The University of Texas System (53, 6.07%) was the most productive institution. Integrating these results of hotspot and frontier analysis, TSA-based mIHC/IF provides significant benefits, particularly in neurology, cancer and immunology.ConclusionThis study conducted a comprehensive bibliometric analysis for the use of TSA-based mIHC/IF. As TSA-based mIHC/IF and its associated imaging systems and analytic software progress, it will become the most promising tool for describing the variety of the whole tissue for a better understanding of pathological or physiological behavior.

Programmed death-ligand 1 (PD-L1) carried by tumor-derived exosomes has emerged as a critical mediator of immune evasion and resistance to immune checkpoint blockade therapy. Unlike membrane-bound PD-L1, exosomal PD-L1 is systemically distributed and capable of suppressing T cell activity at distant sites. This review summarizes the current understanding of exosomal PD-L1 biogenesis, its immunosuppressive mechanisms, and its clinical relevance across multiple cancer types. We highlight its potential as a non-invasive biomarker for predicting therapeutic response and monitoring disease progression. Compared with tissue-based PD-L1 assessment, exosomal PD-L1 offers advantages in accessibility and dynamic reflection of tumor immune status. However, challenges remain regarding standardization of detection methods and clinical interpretation. Future directions include the integration of exosomal PD-L1 profiling into immunotherapy decision-making and the development of therapeutic strategies targeting exosome secretion. These insights may contribute to overcoming resistance in immunologically inert tumors and advancing precision oncology.

Growing evidence suggests that gut microbiota (GM) plays a role in diabetic retinopathy (DR), but the causal microbial drivers and their stage-dependent roles during DR progression remain poorly characterised. Using genetic causality methods, we aim to depict a longitudinal GM mapping and stage-stratified GM signatures across the DR trajectory, spanning initial background DR (BDR) through non-proliferative form (NPDR), to advanced proliferative stage (PDR). GWAS data of 207 GM taxa (from phylum to species) were acquired from the Dutch Microbiome Project (N = 7,824), and DR from FinnGen (over 300,000 individuals). A bidirectional two-sample Mendelian Randomization (TSMR) analysis was conducted to elucidate directional causality between GM and DR. Multiple sensitivity evaluations were performed for pleiotropy, heterogeneity, and stability. Additionally, two-step MR and multivariable MR (MVMR) were performed to dissect causal GM-DR relationships using 1400 candidate circulating metabolite level/ratio data from a Canadian cohort (N = 8,299). We identified 11 causal GM taxa (1 family, 3 genera, and 7 species) during the progression of DR. Notably, species_Bacteroides_dorei and species_Dorea_longicatena demonstrated pan-stage pathogenicity (BDR and PDR, all OR>1, PIVW<0.05), while family_Clostridiaceae (OR = 1.540, 95

PTPN14 is a non-receptor tyrosine phosphatase that functions as a tumor suppressor through negative regulation of the Hippo signaling pathway, making it a potential therapeutic target for cancer. Despite its therapeutic potential, no PTPN14-targeting drugs have been developed to date. In this study, we discovered fenofibrate (FF), a small-molecule commonly used as a lipid-lowering agent, exhibits potent anti-proliferative and anti-migratory properties. Mechanistically, FF was found to directly bind the PPxY motif of PTPN14, facilitating formation of a complex with LATS1 and MARK3, which promotes cytoplasmic sequestration of YAP. Furthermore, genetic knockdown of PTPN14 or pharmacological inhibition of MARK3 substantially abolished the FF-mediated inhibition of malignant phenotypes, indicating the critical role of the PTPN14/MARK3/Hippo signaling axis in tumor progression. Notably, our findings demonstrate that FF enhances the antitumor effects of conventional chemotherapeutics in melanoma, colorectal carcinoma, and ovarian carcinoma. These results establish PTPN14 as a therapeutically actionable target and expand the clinical potential of FF beyond its metabolic applications, offering a novel strategy for cancer treatment.

Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed late. In ovarian cancer, multiple metabolic enzymes of lipid metabolism are abnormally expressed, resulting in metabolism disorder. As a characteristic pathway in polyunsaturated fatty acid (PUFA) metabolism, arachidonic acid (AA) metabolism is disturbed in ovarian cancer. Therefore, we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes. This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms (TCGA, ICGC, and GSE17260). The high association between the risk subgroups and clinical characteristics indicated a good performance of the model. Our data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian cancer. Deficiency of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian cancer. Additionally, our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis, which contributes to the reduction of tumor-infiltrating CD8+ T cells and immune escape in ovarian cancer. These findings provide new insights into the prognosis and potential target of LTA4H/CCL5 in treating ovarian cancer.

The regulation of PD-L1 is the key question, which largely determines the outcome of the immune checkpoint inhibitors (ICIs) based therapy. However, besides the transcription level, the protein stability of PD-L1 is closely correlated with its function and has drawn increasing attention. In this study, EZH2 inhibition enhances PD-L1 expression and protein stability, and the deubiquitinase ubiquitin-specific peptidase 22 (USP22) is identified as a key mediator in this process. EZH2 inhibition transcriptionally upregulates USP22 expression, and upregulated USP22 further stabilizes PD-L1. Importantly, a combination of EZH2 inhibitors with anti-PD-1 immune checkpoint blockade therapy improves the tumor microenvironment, enhances sensitivity to immunotherapy, and exerts synergistic anticancer effects. In addition, knocking down USP22 can potentially enhance the therapeutic efficacy of EZH2 inhibitors on colon cancer. These findings unveil the novel role of EZH2 inhibitors in tumor immune evasion by upregulating PD-L1, and this drawback can be compensated by combining ICI immunotherapy. Therefore, these findings provide valuable insights into the EZH2-USP22-PD-L1 regulatory axis, shedding light on the optimization of combining both immune checkpoint blockade and EZH2 inhibitor-based epigenetic therapies to achieve more efficacies and accuracy in cancer treatment.

Objective: To review the studies related to keratoconus in China, investigate research hotspots and development trends in this field, and provide reference for future research. Methods: This is a bibliometrics study. The relevant literature written in Chinese was retrieved from the WanFang DATA and the China National Knowledge Infrastructure, English articles were collected from the Web of Science Core Collection database. Searched for journal articles related to keratoconus VOSviewer software, CiteSpace, and Bibliometrix in the R language were employed to create the knowledge map. The analysis encompassed the distribution of published journals, research collaboration networks of countries/regions, institutions, and authors. Additionally, core authors, high-frequency keyword co-occurrence, keyword topic maps, and keyword emergence time ranking were examined. Results: The study ultimately included 1 100 Chinese articles and 668 English articles. Chinese literature and English literature began to increase in 1997 and 2009, respectively, indicating that the field is currently in a developmental stage. The publications involved 244 Chinese journals and 150 English journals, predominantly in the field of ophthalmology. The United States collaborated the most with China, contributing to 123 articles, followed by other countries such as the United Kingdom and Switzerland. Chinese literature and English literature involved 552 and 883 institutions, respectively. The institution with the highest number of Chinese literature publications was the Eye Institute of Shandong First Medical University (63 papers), while Wenzhou Medical University had the highest number of English literature publications (91 papers). Chinese literature involved 2 435 authors, and English literature involved 2 073 authors. The largest collaboration cluster in Chinese literature was formed by the teams of Xie Lixin and Shi Weiyun, while the Gao Hua team formed the largest cluster in English literature. However, collaboration between authors was primarily limited to within each team. A total of 622 and 1 611 keywords were extracted from Chinese and English literature, respectively. The node centrality of the four Chinese keywords, "keratoconus", "cornea", "corneal transplantation" and "myopia" as well as the three English keywords, "keratoconus", "collagen cross-linking" and "penetrating keratoplasty" was greater than 0.1. "Collagen", "riboflavin", "corneal transplantation" and "ultraviolet A" were identified as common core hotspots and important research topics in Chinese and English literature on keratoconus. Keyword emergence analysis indicated that the keywords with the highest intensity of emergence in Chinese and English literature were "myopia" (13.54) and "penetrating keratoplasty" (9.99), respectively. The longest emergence time was observed for "contact lenses" (1995-2006) and "penetrating keratoplasty" (2003-2014). Conclusions: At present, research on keratoconus in China is on the rise, with research hotspots including pathogenesis, various new surgical methods, and improvement in quality of life. The future research trend mainly focuses on early diagnosis and screening methods, artificial intelligence, biomechanical examination, subclinical keratoconus, and small incision lenticule extraction.

Cancer immunotherapy has greatly improved the prognosis of tumor-bearing patients. Nevertheless, cancer patients exhibit low response rates to current immunotherapy drugs, such as PD1 and PDL1 antibodies. Cyclic dinucleotide analogs are a promising class of immunotherapeutic agents. In this study, in situ autologous tumor vaccines, composed of Bis-2′-F-cGSASMP phosphonothioate isomers (FGA-di-pS-2 or FGA-di-pS-4) and cytidinyl/cationic lipids (Mix), were constructed. Intravenous (i.v.) and intratumoral (i.t.) injection of FGA-di-pS-2/Mix or FGA-di-pS-4/Mix enhanced the immunogenic cell death of tumor cells in vivo, leading to the exposure and presentation of whole tumor antigens, inhibiting tumor growth in both LLC and EO771 tumor in situ murine models and increasing their survival rates to 50% and 23%, respectively. Furthermore, the tumor-bearing mice after treatment showed potent immune memory efficacy and exhibited 100% protection against tumor rchallenge. i.v. administration of FGA-di-pS-2/Mix potently promoted DC maturation, M1 macrophage polarization and CD8+ T-cell activation and decreased the proportion of Treg cells in the tumor microenvironment. Notably, two doses of ICD-debris (generated by FGA-di-pS-2 or 4/Mix-treated LLC cells) protected 100% of mice from tumor growth. These tumor vaccines showed promising results and may serve as personalized cancer vaccinations in the future.

Five small interfering RNA (siRNA)-based therapeutics have been approved by the Food and Drug Administration (FDA), namely patisiran, givosiran, lumasiran, inclisiran, and vutrisiran. Besides, siRNA delivery to the target site without toxicity is a big challenge for researchers, and naked-siRNA delivery possesses several challenges, including membrane impermeability, enzymatic degradation, mononuclear phagocyte system (MPS) entrapment, fast renal excretion, endosomal escape, and off-target effects. The siRNA therapeutics can silence any disease-specific gene, but their intracellular and extracellular barriers limit their clinical applications. For this purpose, several modifications have been employed to siRNA for better transfection efficiency. Still, there is a quest for better delivery systems for siRNA delivery to the target site. In recent years, nanoparticles have shown promising results in siRNA delivery with minimum toxicity and off-target effects. Patisiran is a lipid nanoparticle (LNP)-based siRNA formulation for treating hereditary transthyretin-mediated amyloidosis that ultimately warrants the use of nanoparticles from different classes, especially lipid-based nanoparticles. These nanoparticles may belong to different categories, including lipid-based, polymer-based, and inorganic nanoparticles. This review briefly discusses the lipid, polymer, and inorganic nanoparticles and their sub-types for siRNA delivery. Finally, several clinical trials related to siRNA therapeutics are addressed, followed by the future prospects and conclusions.

Advanced ScienceVolume 11, Issue 23 2470136 Inside Back CoverOpen Access EZH2 Inhibition Enhances PD-L1 Protein Stability Through USP22-Mediated Deubiquitination in Colorectal Cancer (Adv. Sci. 23/2024) Jiaqi Huang, Jiaqi HuangSearch for more papers by this authorQianqian Yin, Qianqian YinSearch for more papers by this authorYuqing Wang, Yuqing WangSearch for more papers by this authorXin Zhou, Xin ZhouSearch for more papers by this authorYunyun Guo, Yunyun GuoSearch for more papers by this authorYuanjun Tang, Yuanjun TangSearch for more papers by this authorRui Cheng, Rui ChengSearch for more papers by this authorXiaotong Yu, Xiaotong YuSearch for more papers by this authorJie Zhang, Jie ZhangSearch for more papers by this authorChen Huang, Chen HuangSearch for more papers by this authorZhanya Huang, Zhanya HuangSearch for more papers by this authorJianlin Zhang, Jianlin ZhangSearch for more papers by this authorZhengyang Guo, Zhengyang GuoSearch for more papers by this authorXiao Huo, Xiao HuoSearch for more papers by this authorYan Sun, Yan SunSearch for more papers by this authorYanfang Li, Yanfang LiSearch for more papers by this authorHao Wang, Hao WangSearch for more papers by this authorJianling Yang, Jianling YangSearch for more papers by this authorLixiang Xue, Lixiang XueSearch for more papers by this author Jiaqi Huang, Jiaqi HuangSearch for more papers by this authorQianqian Yin, Qianqian YinSearch for more papers by this authorYuqing Wang, Yuqing WangSearch for more papers by this authorXin Zhou, Xin ZhouSearch for more papers by this authorYunyun Guo, Yunyun GuoSearch for more papers by this authorYuanjun Tang, Yuanjun TangSearch for more papers by this authorRui Cheng, Rui ChengSearch for more papers by this authorXiaotong Yu, Xiaotong YuSearch for more papers by this authorJie Zhang, Jie ZhangSearch for more papers by this authorChen Huang, Chen HuangSearch for more papers by this authorZhanya Huang, Zhanya HuangSearch for more papers by this authorJianlin Zhang, Jianlin ZhangSearch for more papers by this authorZhengyang Guo, Zhengyang GuoSearch for more papers by this authorXiao Huo, Xiao HuoSearch for more papers by this authorYan Sun, Yan SunSearch for more papers by this authorYanfang Li, Yanfang LiSearch for more papers by this authorHao Wang, Hao WangSearch for more papers by this authorJianling Yang, Jianling YangSearch for more papers by this authorLixiang Xue, Lixiang XueSearch for more papers by this author First published: 19 June 2024 https://doi.org/10.1002/advs.202470136AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Graphical Abstract Colon Cancer EZH2 inhibitor can activate the expression of deubiquitinase USP22 in colorectal cancer via canonical epigenetic regulation, thereby stabilizing PD-L1 protein and enhancing its expression, resulting in immune evasion and compromised anti-tumor efficacy. Combination with immunotherapy can overcome the immune suppressive effects of EZH2 inhibitors and achieve better outcome. More details can be found in article number 2308045 by Hao Wang, Jianling Yang, Lixiang Xue, and co-workers. Volume11, Issue23June 19, 20242470136 RelatedInformation

Purpose:This study aimed to investigate causal relationships between gut microbiota, blood metabolites, immune cell traits, circulating inflammatory proteins, and myopia through Mendelian randomization (MR) analysis. Design:Mendelian randomization study. Subjects:Genome-wide association study (GWAS) data of 412 gut microbiota, 1400 blood metabolites/metabolite ratios, 731 immune cell traits, and 91 circulating inflammatory proteins from the public GWAS database. Genome-wide association study data of myopia from the public GWAS database and FinnGen consortium. Methods:Two-sample MR analysis and meta-analysis were employed using 4 methods, with inverse-variance weighted as the primary approach, to investigate potential causal links. Metabolic pathway analysis was conducted to explore metabolic pathways. The Cochran Q-test, MR-Egger intercept test, and MR-PRESSO were used for sensitivity analyses. Mediation and reverse MR analyses were also carried out to identify potential mediation relationships and modification effects of myopia. Main Outcome Measures:Causal relationships between gut microbiota, blood metabolites, immune cell traits, circulating inflammatory proteins, and myopia. Results:We identified causal effects of 34 and 22 gut microbiota/bacterial pathways, 131 and 98 blood metabolites/metabolite ratios, 60 and 37 immune cell traits, and 5 and 2 circulating inflammatory proteins on myopia (ukb-b-6353 and R10_H7_MYOPIA, respectively). Overlapping causal relationships were found for 1 gut bacterial pathway, 10 blood metabolites/metabolite ratios, and 2 immune cell traits across both outcomes; however, none of these overlaps reached significance after meta-analysis. The Small Molecule Pathway Database and Kyoto Encyclopedia of Genes and Genomes database enriched 14 significant pathways. Flavin adenine dinucleotide was involved in 8 pathways in both databases. Furthermore, the causal effect of glycochenodeoxycholate glucuronide on myopia was mediated by acetyl-CoA fermentation to butanoate lI, with mediation proportion of 19.03% (ukb-b-6353) and 19.48% (R10_H7_MYOPIA). Reverse MR analysis identified modification effects of myopia (ukb-b-6353) on gut microbiota, blood metabolites, and circulating inflammatory proteins. Conclusions:These findings demonstrated significant causal relationships between gut microbiota, blood metabolites, immune cell traits, circulating inflammatory proteins, and myopia. Gut microbiota pathway may mediate the causal effects of blood metabolite on myopia. This may provide researchers with a new perspective in exploring the biological mechanisms of myopia and may lead to the exploration of earlier treatment strategies. Financial Disclosures:The author(s) have no proprietary or commercial interest in any materials discussed in this article.