PURPOSE. Nonhuman primates (NHPs) serve as valuable models for human retinal and choroidal diseases related with development and aging. This study aimed to investigate the association among age and thickness of the retina, RPE, and choriocapillaris in cynomolgus macaques. Association of age with choriocapillaris was examined in postmortem human samples. METHODS. Optical coherence tomography images were obtained from 543 eyes from 285 macaques aged 0.78 to 22.4 years. The association between age and thickness of retinal and subretinal layers were examined using piecewise linear mixed effects models. Choriocapillaris thickness was assessed microscopically in postmortem human globes from 24 individuals aged 11 to 82 years. RESULTS. Before age 4 years (equivalent to 12 years in humans), total retinal thickness and ganglion cell layer, inner nuclear layer, and parafoveal outer nuclear layer thickness were positively associated with age, whereas after age 4 years, thicknesses of these layers were negatively associated. Age was negatively associated with retinal nerve fiber layer and foveal outer nuclear layer thickness, but positively with thicknesses of RPE/Bruch's membrane and choriocapillaris layers throughout the entire age range. Analysis of postmortem human specimens demonstrated a positive correlation between choriocapillaris diameter and age. CONCLUSIONS. Cynomolgus macaques undergo thickening of multiple retinal layers through their juvenile stage. Afterward, macaques undergo thinning of multiple retinal layers with age, suggesting aging-related changes. The increase in choriocapillaris thickness with age in both macaques and humans suggest remodeling due to aging. Cynomolgus macaques represent a valuable NHP model for studying developmental-and aging-related retinal/subretinal changes.

PURPOSE. To characterize sex-specific and offspring number-associated patterns of ocular aging in Macaca fascicularis. METHODS. Comprehensive ophthalmic examinations were performed on 94 adult macaques (47 males, 47 females). Ocular biometry (lens thickness [LT], anterior chamber depth [ACD], axial length), nuclear lens density (NLD), macula retinal thickness, and retinal nerve fiber layer thickness (RNFLT) were assessed using IOLMaster and swept-source optical coherence tomography. Cataract and drusen were diagnosed using clinical imaging criteria. Sex-specific age associations were examined using correlation. Offspring number analyses included 16 females and 24 males with confirmed reproductive records. RESULTS. Females and males differed significantly in ocular dimensions, with females showing smaller eyes and thinner retinas. Cataract prevalence was significantly higher in females compared to males (19.2% vs. 4.3%, P = 0.0286), whereas drusen prevalence was similar between sexes (17.0% in females vs. 14.9% in males). Although NLD and LT increased and ACD decreased with age in both sexes, aging slopes were consistently steeper in females. Increasing offspring number was associated with significant reductions in RNFLT in females, independent of age, while lens-related parameters showed no significant association with offspring number in either sex. CONCLUSIONS. Female macaques exhibit accelerated lens aging and increased cataract susceptibility, mirroring patterns observed in human populations. Offspring number selectively contributes to neuroretinal thinning, suggesting a reproductive influence on retinal decline that is distinct from lens aging. These findings highlight the importance of considering sex and reproductive history in NHP-based ocular aging studies and provide biological insights relevant to human age-related eye disease.

Microglia are central regulators of retinal immune homeostasis, yet their pathogenic states in retinal degeneration remain less well understood. Here we identified a distinct subset of lipid-accumulated reactive microglia (aLARM), using scRNA sequencing and spatial transcriptomics in NaIO3-induced retinal degeneration mice, predominantly localized to the outer retina. aLARM were conserved across mouse models and patients and uniquely marked by high CD36 expression. Microglia-specific CD36 deletion abolished aLARM-mediated inflammation and degeneration, whereas subretinal transplantation of CD36+ aLARM exacerbated retinal structural destruction and functional impairment. Mechanistically, CD36+ aLARM activated NLRP3 inflammasome and produced IL-1β, engaging IL-1R1 on microglia/macrophages and pericytes/SMCs to amplify a feed-forward inflammatory circuit. Therapeutic CD36 blockade with the neutralizing antibody FA6-152 reduced aLARM formation and protected against neurodegeneration. Together, our findings highlight CD36+ aLARM as a targetable pathogenic microglial population linking neuroinflammation to retinal degeneration, providing a potential foundation for microglia-based precision therapies. Metabolic stress can reshape immune cells into drivers of tissue damage. This study identifies CD36-driven lipid accumulation in reactive microglia as a mechanism linking retinal inflammation to degeneration.

Purpose:Wet age-related macular degeneration is a leading cause of irreversible vision loss, primarily due to choroidal neovascularization (CNV) and subsequent fibrosis. Although current anti-vascular endothelial growth factor A (anti-VEGF) therapies offer significant benefits, many patients exhibit limited or no response and develop drug resistance over time, necessitating the exploration of complementary or alternative therapeutics. This study aimed to identify and characterize a platelet-derived growth factor-C (PDGF-C)-targeting DNA aptamer and to evaluate its therapeutic potential for suppressing CNV and fibrosis, including in an anti-VEGF-refractory setting. Methods:A DNA aptamer against PDGF-C (α-PC aptamer) was identified using systematic evolution of ligands by exponential enrichment. Its binding to PDGF-C and inhibition of PDGF-C/platelet-derived growth factor receptor alpha (PDGFRα) interaction were assessed using surface plasmon resonance. The effects of the α-PC aptamer on PDGF-C-induced proliferation, migration, and PDGFRα, Akt, and extracellular-regulated kinase (ERK) signaling were examined in fibroblasts and human umbilical vein smooth muscle cells (HUVSMCs). In vivo efficacy was evaluated in a laser-induced CNV mouse model, including anti-VEGF refractory aged mice. Results:The α-PC aptamer specifically bound to PDGF-C and effectively blocked its binding to PDGFRα. The α-PC aptamer significantly inhibited PDGFRα, Akt, and ERK activation and suppressed PDGF-C-induced proliferation and migration of both fibroblasts and HUVSMCs. Importantly, in a laser-induced CNV mouse model, the α-PC aptamer markedly reduced neovascularization and fibrosis; it particularly retained efficacy in suppressing CNV in anti-VEGF refractory aged mice, where anti-VEGF treatment failed to do so. Conclusions:These findings suggest that the α-PC aptamer represents a promising therapeutic agent for treating neovascular diseases, especially in patients refractory to anti-VEGF treatment.

PURPOSE:To evaluate the prediction accuracy of intraocular lens (IOL) calculation formulas in primary IOL fixation using the Yamane technique and explore adjustment strategies to improve the refractive outcomes. SETTING:Zhongshan Ophthalmic Center, Guangzhou, China. DESIGN:Retrospective case series. METHODS:50 eyes from 50 patients with inadequate capsular support who underwent lens extraction and primary Yamane IOL fixation were reviewed. The predictive accuracy of 7 formulas, Barrett Universal II (BU II), Emmetropia Verifying Optical (EVO), Kane, SRK/T, Holladay 1, Hoffer Q, and Haigis, was evaluated with or without lens constant optimization. RESULTS:Before lens constants optimization, SRK/T, Holladay 1, Hoffer Q, BU II, and EVO formulas exhibited statistically significant hyperopic mean prediction errors (PEs) (range 0.26 to 0.44 diopters [D], all P < .05), whereas the Haigis and Kane formulas showed relatively better accuracy without significant hyperopic shift. The mean absolute error (MAE) of all formulas ranged from 0.47 to 0.65 D, and the percentage of eyes with PE with ± 0.50 D ranged from 40% to 60%. After lens constants optimization, the BU II and SRK/T formulas exhibited the lowest MAE (0.43 and 0.47, respectively), with the highest percentage of PE within ± 0.50 D (64% and 64%, respectively). CONCLUSIONS:Before lens constant optimization, BU II, EVO, SRK/T, Holladay 1, and Hoffer Q all produced significantly hyperopic PEs in primary Yamane IOL fixation. After lens constants optimization, the BU II and SRK/T displayed better performance. To enhance refractive outcomes in these patients, a slightly myopia target refraction or optimization of the lens constants was recommended.

Purpose:Retinal pigment epithelial (RPE) dysfunction is a central pathological feature of retinal degenerative diseases, leading to irreversible vision loss. RPE dysfunction is substantially driven by mitochondrial impairment and senescence. However, the upstream regulators of these processes remain largely undefined. This study investigated the role of neuropilin-2 (NRP2) in RPE homeostasis and explored mitochondrial-targeted therapy with echinacoside (ECH) as a potential intervention for retinal degeneration. Methods:RPE-specific Nrp2 conditional knockout mice were generated using AAV-VMD2-Cre and retinal morphology and function were assessed by fundus imaging, optical coherence tomography, histology, and electroretinogram (ERG). Cellular and metabolic phenotypes were examined in NRP2-deficient ARPE-19 cells and validated in vivo. RPE senescence, mitochondrial function, NAD⁺ metabolism, and sirtuin activity were analyzed, and the effects of ECH treatment were evaluated both in vitro and in vivo. Results:RPE-specific Nrp2 deletion resulted in progressive RPE atrophy, photoreceptor loss, and impaired ERG responses. NRP2 deficiency led to mitochondrial elongation, elevated ROS, membrane depolarization, and reduced NAD⁺/NADH ratios. Decreased NAD⁺ levels were accompanied by downregulation of SIRT1/SIRT3 and increased protein acetylation, promoting RPE senescence. Restoring NAD⁺ levels or ECH treatment rescued mitochondrial dysfunction and reduced senescence markers in vitro. Furthermore, in vivo ECH administration preserved retinal structure and visual function in NRP2-deficient mice. Conclusions:NRP2 is a critical regulator of mitochondrial integrity and NAD⁺ metabolism in the RPE. Its loss disrupts metabolic homeostasis, promoting RPE senescence and retinal degeneration. Targeting the NRP2-mitochondria-NAD⁺ axis with echinacoside represents a promising therapeutic strategy for preventing retinal degenerative diseases.

Background: Microglial activation is a hallmark of retinal neurodegeneration. However, whether microglia predominantly drive inflammatory damage or support tissue adaptation after acute photoreceptor injury remains unclear. Resolving this issue is critical for defining therapeutic strategies. As colony-stimulating factor 1 receptor (CSF1R) signaling is essential for microglial survival, its pharmacological inhibition enables selective microglial depletion in vivo. Here, we used the CSF1R inhibitor PLX5622 in the N-methyl-N-nitrosourea (MNU) model to directly test the contribution of microglia to inflammation and photoreceptor degeneration. Methods: C57BL/6J mice received PLX5622 for 14 days before and throughout a 5-day MNU regimen. Retinal structure was assessed by fundus photography, optical coherence tomography (OCT), and hematoxylin and eosin (H&E) histology. Visual function was evaluated via electroretinography (ERG). Global transcriptomic alterations were profiled by RNA-seq, and selected inflammatory and complement mediators were assessed by Western blot. Results: PLX5622 treatment resulted in near-complete depletion of TMEM119+/Iba1+ microglia in MNU-injured retinas. Microglia depletion was associated with reduced fundus white lesions, preserved outer nuclear layer (ONL) thickness and nuclei density, and significantly rescued ERG a- and b-wave amplitudes. Transcriptomic analysis further revealed broad attenuation of pro-inflammatory and innate immune pathways, accompanied by modulation of antioxidant responses, mitochondrial/metabolic alterations, neuron-related signaling, and macroglial activation-related programs. Consistently, Western blot analysis confirmed that MNU-induced upregulation of IL-1β, C3, and C1qa was markedly reduced following PLX5622 treatment. Conclusions: Pharmacological CSF1R inhibition leading to efficient retinal microglial depletion attenuated neuroinflammatory responses and preserved photoreceptor structure and visual function in acute toxic retinal degeneration. These findings indicate that microglial activation functions predominantly as a pathogenic amplifier rather than an adaptive response in this context, and identify CSF1R-dependent myeloid signaling as a key mechanistic driver of injury-associated retinal degeneration.

Purpose: To identify non-fundus visual prognosis indicators in cataract patients with congenital iridochoroidal coloboma. Methods: Medical records of patients with congenital iridochoroidal coloboma who underwent cataract surgery were reviewed. Data collected included corrected distance visual acuity (CDVA), axial length, corneal diameter, cataract grade, and intraoperative and postoperative complications. Poor postoperative visual outcome was defined as CDVA＞1.0 logMAR at 1 month postoperatively. Logistic regression was performed to identify potential risk factors for poor visual outcomes. Results: A total of 42 eyes from 36 patients were included. The mean age at surgery was (45.4 ± 8.2) years, and the mean follow-up was (7.2 ± 3.8) months. Intraoperative complications included posterior capsule rupture (PCR) in 2 eyes and zonular dialysis (ZD) in 6 eyes. Postoperative complications included intraocular lens dislocation in 2 eyes and retinal detachment in 1 eye. CDVA improved significantly from (1.50 ± 0.35) logMAR preoperatively to (0.80 ± 0.52) logMAR at 1 month postoperatively (P＜0.001) and (0.79 ± 0.53) logMAR at the final visit (P＜0.001). Logistic regression analysis revealed that poor postoperative visual outcomes were associated with poor preoperative CDVA (OR = 16.01, 95% CI: 1.38 to 185.40, P = 0.026), and microcornea (OR =18.65, 95% CI: 1.45 to 240.52, P = 0.025). Conclusions: Poor preoperative CDVA and the presence of microcornea are significant predictors of poor postoperative visual outcomes in patients with congenital iridochoroidal coloboma.

Mitochondrial dysfunction is a hallmark of aging and a key contributor to age-related diseases including cardiovascular disease. However, molecular pathways that safeguard mitochondrial homeostasis in the aging heart remain poorly understood. Here, we identify MTFR1L as a regulator of mitophagy that binds p-S65-Ub, a key signal amplifying the PINK1/Parkin axis. We find that MTFR1L is enriched in metabolically active tissues, particularly in the heart, where it regulates Parkin signaling. Genetic deletion of Mtfr1l in mice impairs stress-induced mitophagy and Parkin activation, leading to accumulation of damaged mitochondria, increased inflammation and senescence, and accelerated age-related cardiac dysfunction. Strikingly, cardiac expression of MTFR1L progressively decreases along with aging in mice, primates, and humans, coinciding with cardiomyocyte senescence and lipofuscin accumulation. Together, these findings uncover a role for MTFR1L in regulation of the p-S65-Ub/Parkin mitophagy axis and maintenance of mitochondrial homeostasis during cardiac aging and suggest that age-associated loss of MTFR1L may contribute to age-related cardiac dysfunction. Based on these findings, we propose a therapeutic paradigm for the prevention of heart aging by restoring MTFR1L function.

Purpose:Progressive dysfunction of retinal pigment epithelium (RPE) cells is a crucial factor for retinal degeneration, leading to irreversible blindness with limited therapeutic options. Cellular senescence of RPE cells and inflammation are important hallmarks for retinal degeneration, but the underlying molecular mechanisms and potential interventions remain largely unexplored. This study aims to explore whether the IL-6/ IL-6R axis establishes a senescence-inducing circuit in RPE cells, and to evaluate the therapeutic efficacy of its inhibition in rescuing senescent RPE cells and degenerative retina. Methods:Sodium iodate (NaIO₃)-induced retinal degeneration mouse models were established and subjected to intravitreal injections of IL-6 neutralizing antibody, or an IL-6R inhibitor tocilizumab, respectively. Conditional deletion of Stat3 in RPE cells was achieved via subretinal delivery of AAV vectors. RPE cells were isolated for single-cell RNA sequencing (scRNA-seq), qPCR, Western blotting, and immunofluorescence staining. Retinal structure and function were assessed using optical coherence tomography (OCT), hematoxylin and eosin (H&E) staining, and electroretinography (ERG). Results:RPE underwent cellular senescence in NaIO3-induced degeneration, which was dependent on activation of the IL-6/IL-6R axis. IL-6 promoted the senescence of RPE and exacerbated retinal degeneration. In contrast, inhibition of IL-6 suppressed RPE senescence and facilitated recovery of retinal structure and function. Mechanistically, STAT3 activation was essential for IL-6-mediated cellular senescence. Notably, tocilizumab effectively blocked the IL-6/IL-6R/STAT3 signaling cascade, attenuated RPE senescence, and protected against retinal degeneration, expanding the indications of tocilizumab. Conclusions:IL-6 and IL-6R/STAT3 signaling played an essential role in RPE senescence, and tocilizumab presents a translational opportunity in treating retinal degenerative diseases.

Inherited retinal degenerations (IRDs) are important causes of progressive, irreversible blindness. Hereditary macular diseases, in particular, are significant in their effect on the specialized, central cone photoreceptor-rich macula responsible for high resolution vision. Autosomal dominant Best vitelliform macular dystrophy (BVMD), caused by variants in the BEST1 gene, is one of the most common inherited macular dystrophies. Gene therapies have emerged as promising treatments for IRDs, but a lack of suitable animal models has hindered progress both in treatments and in understanding the mechanisms underlying macular diseases. Here, we report a Macaca fascicularis carrying a heterozygous potential pathogenic BEST1p.Q327E variant that disrupts the BEST1 ion channel by destabilizing the A195 helix, mirroring the structural perturbations seen in certain human pathological mutants. Longitudinal imaging over 2 years revealed progressive macular changes, including subfoveal cleft enlargement, lipid-rich deposit accumulation, retinal pigment epithelium (RPE) disruption, and central-to-peripheral photoreceptor degeneration, recapitulating early human BVMD pathology. Histopathology demonstrated diminished BEST1 expression, attenuation of the RPE-photoreceptor interface, and 2 distinct types of lipid deposits, including heretofore unappreciated cone mitochondrial-enriched lesions, highlighting selective cone mitochondria vulnerability. This is, to our knowledge, the first nonhuman primate model of inherited macular dystrophy, and it links BEST1 mutations, mitochondrial dysfunction, and progressive macular degeneration, offering new insights into BVMD pathophysiology and highlighting its utility for studying disease progression and potential therapeutic interventions.

Purpose:Beyond the clinically apparent damage to the retinal vasculature, diabetes affects the neuroretina and choroid. Nonhuman primates (NHPs) serve as valuable models for human retinal diseases, including diabetic retinopathy. This study aimed to investigate changes in the thickness of the retina, RPE, and choriocapillaris in spontaneously diabetic cynomolgus macaques. Methods:Optical coherence tomography (OCT) images were obtained from 25 diabetic macaques and 26 age-matched nondiabetic macaques. The thickness of individual retinal layers in the macula, along with RPE and choriocapillaris, was measured manually. Choriocapillaris thickness was assessed in postmortem human globes from diabetic and nondiabetic individuals. Results:Diabetes predominantly affected the inner retina more than the outer retina in macaques. Notably, the nasal retina showed greater thinning compared to the temporal retina. A slight but significant thickening of the inner nuclear layer was observed. No changes were detected in the thickness of RPE/Bruch's membrane complex via OCT. However, a significant increase in choriocapillaris thickness was noted in the diabetic macaques. Postmortem human specimens from patients with nonproliferative diabetic retinopathy (NPDR) also demonstrated thickening of choriocapillaris/Bruch's membrane. Conclusions:Consistent with humans, early diabetes in cynomolgus macaques results in notable alterations in retinal thickness, particularly affecting the nasal inner retina. The observed increase in choriocapillaris thickness in both diabetic macaques and human patients with NPDR likely indicates pathologic changes and remodeling due to diabetes. Cynomolgus macaque presents a valuable NHP model for studying diabetic retinopathy.

OBJECTIVE:To investigate the role and underlying mechanism of Methyl-CpG binding domain protein 2 (MBD2) in the pathogenesis of acute respiratory distress syndrome (ARDS)-related pulmonary fibrosis. METHODS:Murine models for ARDS-related pulmonary fibrosis were established in wildtype or MBD2 knockout mice, expressions of MBD2 were determined with immunohistochemistry (IHC), immunofluorescence, and western blot. Epithelial-to-mesenchymal transition (EMT) was detected with determined with decreased expression of E-cadherin and increased expressions of N-cadherin, Vimentin, and α-smooth muscle actin (α-SMA). Transforming growth factor β (TGF-β) treated mouse lung epithelial-12 (MLE-12) cells and primary human type II alveolar epithelial cells were applied to establish in vitro model for EMT. Transcriptional sequencing with RNA-Seq and Chromatin immunoprecipitation (ChIP) assay were used to explore the potential targets of MBD2. Single cell sequencing data and Human pulmonary fibrosis samples were analyzed. RESULTS:Bleomycin (BLM) and lipopolysaccharide (LPS) induced EMT, pulmonary fibrosis, and increased expression of MBD2 in alveolar epithelial cells of mice, and MBD2 knockout significantly alleviated BLM- and LPS-induced pulmonary fibrosis and EMT. TGF-β induced EMT and elevated MBD2 expressions in alveolar epithelial cells, which was mitigated by MBD2 knockdown and aggravated by MBD2 overexpression. Frizzled 2 (FZD2) was found to be the potential target of MBD2. Single-cell sequencing analysis of ARDS patients suggested elevated expression of MBD2 in alveolar epithelial cells, and MBD2 expression was elevated in the lungs of patients with pulmonary fibrosis. CONCLUSION:Our results indicated that MBD2 could promote EMT and ARDS-related pulmonary fibrosis, potentially by modulating the expression of FZD2.

PURPOSE:To objectively evaluate the alteration of interdigitation zone (IZ) length in diabetic patients and to determine its relationship with diabetic retinopathy (DR) progression. DESIGN:Prospective cohort study. METHOD:Two hundred and thirty-one diabetic patients (231 eyes) were included. DR was graded according to the modified Airlie House classification system. The high-resolution spectral-domain optical coherence tomography (SD-OCT) images were obtained to calculate the length of IZ using Image-Pro Plus. Linear regression analysis and logistic regression analysis were performed to determine the associations between IZ length with DR severity and DR progression. RESULTS:IZ length was significantly reduced in DR patients compared to that in diabetic patients without DR (NDR) (3.758 ± 1.653 mm vs 5.722 ± 0.865 mm, P < .001). After adjusting for confounding factors, IZ length showed a negative association with DR severity, and longer IZ length correlated with better best corrected visual acuity (BCVA) (ß -0.021, 95% CI -0.030 to -0.011, P < .001). Forty eyes (21.98%) developed DR progression over 3-year follow-up. Notably, longer IZ length at baseline was associated with lower risk of DR progression over 3-year follow-up (OR 0.039, 95% CI 0.011-0.139, P < .001). The logistic regression models predicted DR progression with area under the curve (AUC) of 0.917 (95% CI 0.872-0.962) and 0.953 (95% CI 0.917-0.989) respectively based only on IZ length and IZ length combined with established risk factors. CONCLUSIONS:IZ length decreased with DR severity and significantly correlated with DR progression, potentially serving as a new predictor for disease progression.

Purpose: To objectively quantify posterior capsule opacification (PCO) using swept-source anterior segment optical coherence tomography (SS-AS-OCT) in pseudophakic eyes. Setting: Zhongshan Ophthalmic Center, Guangzhou, China. Design:Prospective cross-sectional study. Methods: 180 eyes with PCO (37 multifocal intraocular lenses [mfIOLs] and 143 monofocal intraocular lenses [moIOLs]) were enrolled. The PCO irregular degree (PID), defined to evaluate the surface irregularity of PCO, the average and maximum thickness of PCO (AT-PCO, MT-PCO) were applied to quantify PCO based on SS-AS-OCT (CASIA2) images. Corrected distance visual acuity (CDVA), higher-order aberrations (HOAs), modulation transfer function, and Strehl ratio were recorded. The associations between SS-AS-OCT parameters and visual function parameters were assessed by Spearman correlation analysis. Results: PID, AT-PCO, and MT-PCO showed significant correlations with CDVA, Strehl ratio, and HOAs (CDVA: r = 0.702, 0.741, and 0.736; Strehl ratio: r = -0.746, -0.719, and -0.740; HOAs: r = 0.762, 0.734, and 0.752). The correlations of these 3 parameters with Strehl ratio and HOAs were significantly higher than those of clinical PCO grading with Strehl ratio and HOAs (all P < .05). Particularly, PID demonstrated notable correlations with Strehl ratio and HOAs. In addition, patients with mfIOLs presented worse Strehl ratio and HOAs than those with moIOLs after matching age, PID, AT-PCO, and MT-PCO. Conclusions: This study provides a new method for objectively quantifying PCO using successive cross-sectional SS-AS-OCT images. AT-PCO, MT-PCO, and PID are presented as new indicators to document PCO severity, with PID offering a unique perspective by considering the irregularity aspect of PCO.

Optic neuropathies, characterized by injury of retinal ganglion cell (RGC) axons of the optic nerve, cause incurable blindness worldwide. Mesenchymal stem cell–derived small extracellular vesicles (MSC-sEVs) represent a promising “cell-free” therapy for regenerative medicine; however, the therapeutic effect on neural restoration fluctuates, and the underlying mechanism is poorly understood. Here, we illustrated that intraocular administration of MSC-sEVs promoted both RGC survival and axon regeneration in an optic nerve crush mouse model. Mechanistically, MSC-sEVs primarily targeted retinal mural cells to release high levels of colony-stimulating factor 3 (G-CSF) that recruited a neural restorative population of Ly6C low monocytes/monocyte-derived macrophages (Mo/MΦ). Intravitreal administration of G-CSF, a clinically proven agent for treating neutropenia, or donor Ly6C low Mo/MΦ markedly improved neurological outcomes in vivo. Together, our data define a unique mechanism of MSC-sEV-induced G-CSF-to-Ly6C low Mo/MΦ signaling in repairing optic nerve injury and highlight local delivery of MSC-sEVs, G-CSF, and Ly6C low Mo/MΦ as therapeutic paradigms for the treatment of optic neuropathies.