Blood-retinal barrier (BRB) destruction and inflammatory response are key contributors to the pathogenesis of various chronic ocular diseases including non-infectious uveitis, diabetic retinopathy, age-related macular degeneration, and retinal vein occlusions [[1], [2], [3], [4], [5]]. Chronic non-infectious uveitis, an immune-mediated chronic intraocular inflammatory disorder, accounts for 5–20 % of irreversible blindness cases worldwide [6,7]. Current treatments include frequent administration of corticosteroids, immunosuppressive agents, and biological therapies [8,9]. However, long-term and systemic administration of such drugs can lead to various side effects, including infection, hepatic or renal injury, hypertension, and osteoporosis. Moreover, conventional treatments, such as systemic medications and eye drops, are ineffective at delivering drugs to the posterior segment of the eye due to ocular barriers and biological clearance [10]. Intravitreal injection can overcome these barriers, enabling drugs to reach the posterior segment; however, it has various limitations such as the need for repeated injections, poor patient compliance, and potential complications. Thus, there is a critical need to improve targeted drug delivery to the site of the origin of the disease, rather than simply overcoming ocular barriers.

Future therapeutic strategies involve precision medicine, which involves targeting specific pathophysiological processes on an individual basis. Considering uveitis in particular, an effective and safe therapeutic approach is required for its treatment. Microglia play a key role in retinal homeostasis and have pleiotropic effects on initiating and transforming inflammatory responses, as well as forming and maintaining BRB [11,12]. Okunuki et al. demonstrated that microglia are essential for initiating immune cell infiltration in a murine model of experimental autoimmune uveoretinitis (EAU) [13]. In our previous study, we found that inhibiting microglial activation suppressed leukocyte infiltration and preserved the integrity of BRB during EAU development and progression [14]. Furthermore, aberrant T cell-mediated immune imbalances, particularly T helper 1 and 17 (Th1 and Th17) responses, are central to human and animal uveitis [[15], [16], [17]]. Interleukin-17 (IL-17), primarily secreted by Th17 cells [18], promotes inflammation by targeting the retinal pigment epithelium (RPE) cells, contributing to the inflammatory microenvironment in the eye [19]. RPE cells play a crucial role in maintaining BRB integrity and regulating immune response within the eye, modulating T cell responsiveness [20,21]. Upon stimulation by IL-17 signals, the RPE cells activate pathways such as the Akt, Erk1/2, p38 MAPK, and NF-κB signalling and form NLRP3 inflammasomes [22]. In the therapeutic management of human uveitis, subcutaneous administration of the anti-IL-17 monoclonal antibody secukinumab (SEK) has shown benefits to a certain extent, primarily in reducing the use of concomitant immunosuppressive medication [23]. This study reported no statistically significant differences in uveitis recurrence between the subcutaneous SEK and placebo groups. A subsequent, multicentre, randomised, double-masked, dose-ranging trial revealed higher responder rates (72.7 % and 61.5 % vs. 33.3 %) and remission rates (27.3 % and 38.5 % vs. 16.7 %) when using intravenous SEK (30 and 10 mg/kg) compared with subcutaneous SEK (300 mg) [24]. These findings underscore the importance of high drug doses and specific administration routes for the therapeutic efficacy of SEK in non-infectious uveitis. However, high-dose systemic administration is often associated with more adverse events.

Nanocarriers offer an alternative strategy for achieving high drug concentrations in local pathogenic tissues for the treatment of chronic posterior ocular disease. Nguyen et al. developed resveratrol/metformin nanotherapeutics with high retinal permeability and sustained bioactive delivery for treating macular degeneration [25]. Toit et al. synthesised poly(lactic-co-glycolic acid) (PLGA) nanoparticles for controlled delivery of the p11 anti-angiogenic peptide to prevent neovascularisation [26]. Peptide-based nanohydrogels are a promising option owing to their simplicity, scalability in mass production, and favourable biocompatibility; hence, they have garnered extensive attention in the field of drug-delivering systems [[27], [28], [29]]. These hydrogels can form via π–π stacking interactions among peptides with specific amino sequences; this unique property endows them with injectable, self-assembling characteristics, facilitating seamless integration with a diverse range of drugs [30,31]. Furthermore, they offer a feasible approach for direct intraocular delivery, which is essential for intraocular antibody therapeutics [32]. Additionally, the high internal water content of the cross-linking system protects drugs from internal damage, rendering them useful for antibody storage and delivery. Previous studies demonstrated that D/L tetrapeptide hydrogels can enhance antigen uptake and absorption by antigen-presenting cells [28,33].

Building on these findings, in this study we aimed to achieve high intraocular drug concentrations, minimise administration frequency, and reduce systemic drug side effects. We synthesised a peptide-based nanohydrogel co-assembled with SEK to explore the intraocular therapeutic treatment targeting RPE cells. The therapeutic efficacy of a single intravitreal injection was assessed in an EAU rat model. Co-assembled nanofibers with peptide ligands targeted the RPE cells, enhancing uptake and attenuating intraocular inflammation. These methods may also be beneficial for other chronic posterior segment diseases, such as age-related macular degeneration, diabetic retinopathy, and retinal vein occlusions, where complex ocular barriers limit medication delivery and bioavailability [34,35]. Our findings demonstrate that targeted delivery of therapeutic drugs to the retina is crucial for improving bioavailability, reducing administration frequency, and minimising treatment side effects.