Noninfectious uveitis, a subtype of uveitis, seriously impairs vision and can even cause blindness without proper medical management (Dick et al., 2018, Hsu et al., 2019, Thorne et al., 2016). Unlike infectious uveitis, which is normally driven by viruses, bacteria, and protozoa, noninfectious uveitis is presumed to be an autoimmune disorder associated with the dysfunction of innate and adaptive immune responses (Huang and Brown, 2022, Maleki et al., 2022, Rabiah and Vitale, 2003, Sallam et al., 2011, Thomas, 2019). During the pathogenesis of noninfectious uveitis, an external stimulus activates the T helper (Th) 1 immune response, followed by the disruption of blood-retinal barrier and recruitment of circulating inflammatory leukocytes into the eyeballs, thereby causing irreversible tissue damage and visual loss (Atan et al., 2010, Takeuchi et al., 2021, Zarranz-Ventura et al., 2014). Glucocorticosteroids (GCs), acting as robust anti-inflammatory agents, remain the mainstay for the clinical management of noninfectious uveitis via systemic or local administration (Airody et al., 2016, Pohlmann et al., 2018, Tomkins-Netzer et al., 2014, Zarranz-Ventura et al., 2014). Because of severe systemic adverse effects, including hypertension, hyperlipidemia, and diabetes, long-term GCs medication was greatly limited (Daniel et al., 2017, Knickelbein et al., 2015, Ormaechea et al., 2019, Saraiya and Goldstein, 2011, Xiong et al., 2018). As an alternative, local GCs medications (such as topical instillation, periocular injection, and intravitreal injection) avoid systemic adverse effects but present ocular side effects, such as cataract formation and glaucoma (Ganapathy et al., 2018, Li et al., 2021, Valdes and Sobrin, 2020, Wu et al., 2017, Yeh et al., 2019). Considering the pathological mechanism of noninfectious uveitis, there is an urgent need to explore novel immunomodulatory agents for the clinical management of noninfectious uveitis.

Rapamycin (RAPA), also known as sirolimus, is a macrolide with anti-inflammatory, antifungal, and immunosuppressive effects on T cells (Abraham and Wiederrecht, 1996, Heitman et al., 1991, Li et al., 2014). Pilot studies have shown that RAPA is a potent kinase inhibitor that suppresses T-cell proliferation and consequently interrupts the inflammatory cascade (Dumont and Su, 1995, Edinger et al., 2003, Raught et al., 2001). Thus, RAPA may be an effective therapeutic agent for the treatment of noninfectious uveitis (Mehta and Emami-Naeini, 2022). Systemic administration of RAPA via the oral route exhibited great therapeutic efficacy in patients with severe noninfectious uveitis but was associated with serious side-effects. Thus, the local administration of RAPA via subconjunctival and intravitreal injection route was more favorable. Nguyen and colleagues demonstrated that intravitreal injection of RAPA oil formulation at dosage of 440 μg/eye resulted in the improvement in noninfectious uveitis(Merrill et al., 2020). Although the robust therapeutic efficacy of RAPA has been achieved in noninfectious uveitis, the efficient intraocular drug delivery system is an unmet issue.

In the past several decades, various novel drug delivery systems, including micro/nanoparticles, liposomes, and hydrogels, have been developed to realize the robust therapeutic efficacy of rapamycin in various autoimmune disorders (Craparo et al., 2022, Dhanabalan et al., 2020, Falke et al., 2015, Jhunjhunwala et al., 2009, Lei et al., 2022, Li et al., 2022, Shah et al., 2013, Song et al., 2022, Yuan et al., 2008). Previous studies have demonstrated that controlled release depots, such as microparticles and implants, can significantly extend drug retention by incorporating drugs into the polymeric matrix and finely tailor the drug release behavior by modulating its components (Bourges et al., 2006, Kang-Mieler et al., 2020, Yasukawa et al., 2006). Polymeric microparticles are promising vehicles for efficient intraocular drug delivery because of their capacity to solubilize water-insoluble drugs and extend drug release (Brannon-Peppas, 1995, Zimmer and Kreuter, 1995). By exploiting microparticulate drug delivery systems as depots injected into the eyes, we present a promising strategy to overcome the current clinical challenges of long-term immunosuppression and frequent dosing. In this study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., PCEC) for efficient ocular delivery of rapamycin to treat noninfectious uveitis in an EAU rat model. These microparticles were readily fabricated and administered locally into the eye via the subconjunctival injection route, which is expected to provide long-term release of encapsulated rapamycin with minimal side effects.