Anti-VEGF drugs have become the core treatment for NVG. Their pathological mechanism mainly stems from overexpression of Vascular Endothelial Growth Factor-A (VEGF-A) caused by retinal ischemic diseases such as diabetic retinopathy and retinal vein occlusion, which in turn leads to the formation of abnormal neovascularization in the iris and anterior chamber angle, ultimately resulting in angle adhesion, closure, and a sharp increase in intraocular pressure (Rittiphairoj et al., 2023). Studies have shown that intravitreal injection of anti-VEGF drugs can specifically block VEGF-A activity and effectively inhibit the proliferation of vascular endothelial cells. Clinical data indicate that iris neovascularization regresses in more than 85% of patients (Yun et al., 2025). Clinical trials have confirmed that anti-VEGF therapy can significantly reduce intraocular pressure with an average reduction of 7–15 mmHg, while reducing angle adhesion and creating favorable conditions for subsequent surgical treatment (Inatani et al., 2021). In terms of combined therapy, the combination of anti-VEGF drugs with Ahmed Glaucoma Valve Implantation (AGVI) or trabeculectomy can significantly improve surgical success rates. A meta-analysis shows that preoperative use of bevacizumab can increase the success rate of AGVI by 23% (Hwang and Lee, 2021), and postoperative intraocular pressure control is more stable (Lin et al., 2022). Another study confirms that compared with the surgery group, the treatment group receiving anti-VEGF combined with anti-glaucoma surgery has a 35% higher success rate at 6 months after surgery, with a significantly lower incidence of complications (Zhou et al., 2023; Guo et al., 2021). It is worth noting that there are differences in efficacy among different anti-VEGF drugs: a network meta-analysis indicates that aflibercept is superior to ranibizumab in reducing intraocular pressure with a mean difference of 2.1 mmHg, while conbercept performs better in neovascular regression rate with a relative risk of 1.15 (Wang J. et al., 2024). These findings provide an important basis for clinical individualized medication.

Current research has shown that sustained-release technologies can significantly extend the duration of drug action. Sustained-release drug carriers achieve controlled drug release through porous structures or biodegradable materials. As illustrated, the interior of the carrier is divided into multiple independent units, each regulating drug release rate via “sieve pores” (porosity) of different sizes or differentiated degradation rates. This is similar to a ‘layered medicine box’—compartments with larger pores (like wide-mouthed bottles) release drugs quickly at first, while those with smaller pores (like narrow-mouthed bottles) let drugs seep out slowly, ensuring a steady supply over months (So et al., 2025; Li et al., 2025). This design overcomes the drawback of frequent administration required for traditional intravitreal injections, enabling sustained drug concentrations from several weeks to months following a single injection (Long et al., 2024; Lee et al., 2023). As shown in Figure 1, drugs are encapsulated in a large “sustained-release carrier”, which can be hydrogel microspheres, biodegradable implants, or nanoparticles. The drug within the carrier is contained in different small compartments, each equipped with a sieve pore of varying sizes for drug release. The compartment with the largest sieve pore will have its drug released completely first, while the one with the smallest sieve pore allows the slowest drug release. This design ensures that the drug in the carrier can be continuously released into the eye over an extended period after injection, thereby achieving long-term and stable drug concentrations. For different disease conditions and different drugs, the number and size of compartments in the sustained-release carrier, as well as the quantity ratio and size ratio of sieve pores, can be designed accordingly.

For example, bimatoprost-containing hydrogel microsphere carriers can achieve sustained release for 3–6 months, while brinzolamide-containing biodegradable implants can maintain drug efficacy for more than 6 months. This long-acting release property not only avoids the risk of intraocular pressure fluctuations caused by frequent injections but also significantly improves patient compliance (Rodrigo et al., 2021; Ham et al., 2023). In terms of pharmacological mechanisms, prostaglandin analogs promote aqueous humor outflow through the uveoscleral pathway by upregulating matrix metalloproteinases, while carbonic anhydrase inhibitors reduce aqueous humor production by 30%–40% through inhibiting ciliary body carbonic anhydrase. These two mechanisms provide dual guarantees for intraocular pressure control (Soomsawasdi et al., 2025). It is worth noting that intravitreal injection of bone marrow mesenchymal stem cells (MSCs) has shown a protective effect on retinal ganglion cells in animal models of advanced glaucoma, opening up a new avenue for neuroprotective therapy in glaucoma (Vilela et al., 2021). Future development directions need to focus on combined treatment strategies and new delivery systems. Clinical evidence indicates that Adeno-Associated Virus (AAV) vector-mediated Apolipoprotein A-I Binding Protein (AIBP) gene therapy exhibits regulatory effects on retinal cholesterol metabolism and neuroprotective effects in experimental glaucoma (Ju et al., 2025). The latest research has also found that intravitreal injection of anti-High Mobility Group Box 1 (HMGB1) monoclonal antibody can effectively regulate inflammatory responses in animal models of glaucoma, providing a theoretical basis for the development of sustained-release preparations targeting neuroinflammation (Tonner et al., 2022). In terms of technical carriers, the optimized design of hydrogel microspheres and biodegradable implants will further improve the sustained-release performance and targeting of drugs in the vitreous cavity (Prajapati et al., 2021).

The occurrence and development of glaucoma are closely related to intraocular inflammatory changes (Lin and Li, 2025). In terms of anti-fibrotic and anti-inflammatory adjuvant therapy, studies have shown that 0.01% epinephrine can significantly inhibit trabecular meshwork cell contraction by down-regulating the expression of Actin Alpha 2 (ACTA2) gene, and this mechanism can reduce the risk of filtration tract scarring by 50% (Li et al., 2023). Meanwhile, lipid nanoparticle delivery systems targeting the Myocardin-Related Transcription Factor/Serum Response Factor (MRTF/SRF) pathway have shown specific inhibitory effects on trabecular meshwork fibrosis (Luo et al., 2022), and some natural extracts have also been confirmed to antagonize Transforming Growth Factor Beta 2 (TGF-β2)-induced trabecular meshwork cell fibrosis (Wu et al., 2024). Sirtuin 1 (Sirt1) activators exert effects through dual mechanisms: they both inhibit oxidative stress and block Transforming Growth Factor Beta-induced fibrotic signaling pathways (Tie et al., 2025). In the field of anti-inflammatory therapy, anti-Tumor Necrosis Factor Alpha (TNF-α) agents (such as adalimumab) alleviate optic nerve inflammatory damage by inhibiting microglial activation (Meng et al., 2023), which is consistent with the mechanism by which Sesamol regulates neuroinflammation through the AMP-Activated Protein Kinase/Sirtuin 1/Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (AMPK/SIRT1/NF-κB) pathway (Feng et al., 2022). It is worth noting that small interfering RNA for Secreted Protein Acidic and Cysteine Rich (siSPARC) gene silencing technology combined with gelatin hydrogel has shown better anti-scarring effects than mitomycin C in animal models (Chun et al., 2021), providing a new option for surgical adjuvant therapy. In terms of target innovation, existing studies are breaking through the traditional anti-hypertensive framework. In addition to epinephrine, polyphenolic antioxidants have become potential therapeutic targets by protecting the trabecular meshwork from oxidative damage (Sacca et al., 2020), and Matrix Metalloproteinases (MMPs) modulators can simultaneously intervene in trabecular meshwork remodeling and optic nerve protection (Zhang et al., 2023). In the innovation of drug delivery systems, lipid nanoparticles (Luo et al., 2022) and positively charged, tuned gelatin hydrogels (Chun et al., 2021) have significantly improved the intraocular bioavailability of anti-fibrotic drugs. For pressure fluctuations caused by repeated intraocular injections, prophylactic use of anti-glaucoma drugs can reduce the peak intraocular pressure after injection by 35% (Soomsawasdi et al., 2025). These advances have jointly promoted the transformation of intraocular injection from a single treatment to a multi-modal treatment integrating anti-hypertension, anti-fibrosis, and neuroprotection. Among them, the combination strategy of anti- Tumor Necrosis Factor Alpha (anti-TNF-α) agents and anti-VEGF drugs has shown a synergistic effect in neovascular glaucoma (Zhou et al., 2023; Carrola et al., 2021).

A summary of the key mechanisms, efficacy outcomes, and supporting references for the drug categories discussed in this section is provided in Table 1.

In the clinical translation of anti-VEGF therapy, existing studies have confirmed that intravitreal injection of anti-VEGF drugs has a significant effect on NVG. The study shows that a single injection of aflibercept can cause regression of iris neovascularization in 86.7% of NVG patients and reduce the intraocular pressure by an average of 12.3 mmHg (Inatani et al., 2021). Compared with traditional trabeculectomy, anti-VEGF therapy exhibits better safety features. The reported incidence of endophthalmitis is only 0.02%–0.05%, which is significantly lower than the 5%–10% infection risk of filtration surgery. It is worth noting that the combined treatment regimen can further improve the short-term surgical success rate, increasing the intraocular pressure control rate from 68% in simple surgery to 89% (Zhou et al., 2023; He et al., 2024).

Regarding the application progress of sustained-release technology, current research focuses on solving the problem of frequent injections. Experimental sustained-release systems have shown that a single intravitreal implantation of intraocular pressure-lowering drugs can maintain effective concentrations for up to 6 months and can continuously reduce intraocular pressure by 30% in animal models (Rodrigo et al., 2021; Shen et al., 2023). Of particular note is that sustained-release preparations loaded with 5-fluorouracil (5-FU) using nanocarrier technology have demonstrated significant anti-fibrotic effects in applications after glaucoma filtration surgery, increasing the 12-month patency rate of the filtration tract to 91.7%, which is 23% higher than that of traditional intermittent injection regimens (Wang X. et al., 2024; Patel and Sheth, 2021). These technological breakthroughs provide new ideas for reducing injection frequency and improving patient compliance (Masuda et al., 2024).

In terms of combined treatment strategies involving intraoperative adjuvant injection, clinical evidence supports the synergistic effect of MIGS combined with drug therapy. Studies have shown that intraoperative anterior chamber angle injection of epinephrine during iStent implantation can reduce Schlemm’s canal collapse through α1 receptor agonism, resulting in an additional 15.4% reduction in postoperative intraocular pressure (p < 0.01) (Ichioka et al., 2022; Jain and Fan Gaskin, 2025). For high-risk NVG cases, anti-VEGF injection 72 h before surgery can increase the success rate of AGVI from 62% to 84% and reduce intraoperative bleeding (Fan et al., 2023; Sahin et al., 2024). In terms of anti-scarring management, the modified 5-FU sustained-release technology reduces the failure rate of filtration surgery from 38% with conventional treatment to 8% by inducing fibroblast apoptosis, without increasing corneal endothelial cell loss (Wang X. et al., 2024; Fang et al., 2022). These combined regimens are reshaping the treatment paradigm for refractory glaucoma (Siedlecki et al., 2022; Burgos-Blasco et al., 2022).

The core challenge of intravitreal injection in glaucoma treatment lies in the limitations of drug delivery systems. Although current anti-VEGF therapy can effectively control the progression of neovascular glaucoma, its efficacy is highly dependent on the control of primary diseases. Literature shows that the recurrence rate of diabetic retinopathy patients after treatment still exceeds 30% (Zhou et al., 2023). Sustained-release implants can prolong the drug action time, but there is a 5%–8% risk of displacement, and there is a lack of means for real-time monitoring of drug concentrations in aqueous humor (Rodrigo et al., 2021; Hughes et al., 2023). More critically, the relationship between dynamic changes of aqueous humor cytokines and drug responsiveness remains unclear. For example, the concentration of TGF-β2 in aqueous humor of patients with primary open-angle glaucoma is significantly increased, being 2-3 times higher than that in normal individuals, but it is downregulated in secondary open-angle glaucoma (Igarashi et al., 2021; Fujimoto et al., 2023). This complex regulatory network makes the formulation of individualized drug delivery schemes face significant technical bottlenecks (Wu et al., 2025).

The development of breakthrough technologies is focusing on intelligent, responsive delivery systems. Thermosensitive hydrogels can achieve intraocular pressure threshold-responsive drug release through temperature-sensitive polymers, such as chitosan-amino acid complexes. In vitro experiments have confirmed that they can maintain sustained drug release for more than 28 days (Luo et al., 2023; Tong et al., 2022). Nanorobot technology has demonstrated the ability to target and clear fibrotic deposits in the trabecular meshwork in mouse models, and has been shown to reduce intraocular pressure by 35% by activating the Piezo Type Mechanosensitive Ion Channel Component 1 (Piezo1) mechanosensitive channel (Morozumi et al., 2022; Wang et al., 2025). A more cutting-edge Clustered Regularly Interspaced Short Palindromic Repeats and CRISPR-associated protein 9 (CRISPR-Cas9) gene editing combined therapy is being explored. CRISPR-Cas9 works like a “molecular scissors—it can precisely “cut” abnormal genes (such as those overproducing VEGF) and replace them with healthy ones, while also delivering neuroprotective factors to save damaged retinal cells. Through nanocarrier delivery systems, it can achieve the synergistic release of VEGF gene knockout and neurotrophic factors such as Brain-Derived Neurotrophic Factor (BDNF). Animal experiments show that this strategy can increase the survival rate of retinal ganglion cells by 60% (Singh et al., 2025; Deng et al., 2020). These innovative technologies provide new ideas for overcoming the limitations of traditional drug delivery methods (Shen et al., 2023; Corelli, 2021).

Multi-omics technologies are reshaping the paradigm of precise glaucoma treatment. The latest research has found that dynamic changes in aqueous humor biomarker profiles, including IL-6, BDNF, and Transforming Growth Factor Beta (TGF-β), are significantly associated with drug sensitivity. For example, IL-6 trans-signaling can inhibit TGF-β-mediated trabecular meshwork fibrosis (Igarashi et al., 2021; Urahashi et al., 2025). By integrating genomic, proteomic, and metabolomic data, researchers have identified a direct link between mutations in Wingless-type (Wnt) ligand secretion mediator genes and impaired function of the trabecular meshwork (the eye’s key “drainage filter”) (Castillo-Plata et al., 2022). For example, patient-specific trabecular meshwork models—built using induced pluripotent stem cell (iPSC) technology and combined with microfluidic chip systems—act like “miniature eye labs,” allowing doctors to test how a patient might respond to different drugs in a dish before actual treatment (Tian et al., 2020). These tools lay the groundwork for a personalized “treatment-monitoring-adjustment” loop: first, use genetic and molecular data to select the right therapy; then, track biomarkers (such as aqueous humor cytokines) to monitor effectiveness; and finally, adjust the treatment plan based on real-time feedback (Jiang et al., 2025). The optimization of clinical practice requires comprehensive consideration of technological innovation and translational medicine. Existing evidence indicates that anti-VEGF drugs combined with surgery can increase the short-term success rate of neovascular glaucoma patients (Zhou et al., 2023), but attention should still be paid to intraocular pressure fluctuations caused by long-term repeated injections (de Vries et al., 2020; Vilares-Morgado et al., 2023). Future development directions include developing aqueous humor instant detection devices based on quantum dot sensors (Wu et al., 2025), designing degradable drug delivery systems (Kompella et al., 2021), and using artificial intelligence algorithms to integrate multi-modal data for predicting treatment responses (Egger et al., 2025). It is worth noting that interdisciplinary technologies such as self-generating electricity systems have been confirmed in mouse models to achieve automatic intraocular pressure regulation through trabecular meshwork contraction (Wang et al., 2025), which indicates that glaucoma treatment is rapidly moving towards intellectualization, mini-invasiveness, and precision.