Background/Objectives: Diabetic retinopathy is an ocular disease caused by changes in the expression of inflammatory mediators and increased oxidative stress in the retina and is the leading cause of vision loss in diabetic patients. Currently, there is no treatment capable of reversing retinal damage, which represents a significant burden on the quality of life of patients. (1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin stands outs as a prototype of the sp²-iminoglycolipids family for its beneficial neuroprotective effect against this chronic eye disease. Critical issues related to the low solubility and bioavailability of this glycolipid in biological settings are overcome by its encapsulation in a Zeolitic-Imidazolate Framework (ZIF) structure, resulting in homogeneous and biocompatible GlycoZIF nanoparticles. Cell studies show an enhanced cellular uptake compared with the free glycolipid, and importantly, its bioactivity is preserved once released inside cells. Methods: Extensive in vitro and ex vivo assays with diabetic retinopathy models unveil the mechanistic pathways of the designed GlycoZIF. Results: A reduction in proinflammatory mediators, increased heme oxygenase-1 level, inhibition of NLRP3 inflammasome, and reduced reactive gliosis is shown. Conclusions: These findings demonstrate for the first time the potential of Glyco-modified ZIFs for the treatment of diabetes-related ocular problems by controlling the immune-mediated inflammatory response.

(1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin is considered a prominent representative member of the sp2-iminoglycolipid (sp2-IGL) family. Numerous structure-activity relationship studies performed over the years have provided valuable information that allow the validation of the hydrophobic tail of twelve carbon atoms connected to the sulfonyl group as responsible for the immunomodulatory potential. Additionally, recent studies underpin the relevant role played by the glycone space in combination with the validated aglycone fragment to enhance the pharmacological benefits as anti-inflammatory, antiproliferative and leishmanicidal agents. Specifically, replacement of the hydroxyl group placed at C2 of the bicyclic piperidine carbamate scaffold 5N,6O-oxomethylidenenojirimycin by fluorine or hydrogen atoms, as well as the installation of monocyclic aromatic hydrocarbons at O3 position, have considerably improved the therapeutic utility of these glycolipid mimetics as multi-target agents. Building on these findings, novel structural modifications based on nitrogen-functionalities at C2 (azido, amino, acetamido and acetylhydrazino) have been implemented in this work. Biological information collected from in vitro models reveal that the epimeric compounds 8 and 14, which feature the azido group, are the most potent antiproliferative sp2-IGLs in the series. These data are consistent with the remarkable leishmanicidal potential against two species of protozoan parasites of the genus Leishmania (Leishmaniadonovani and Leishmaniamajor). Likewise, research conducted with the 2-azido-2-deoxy derivative 8 in in vitro (retinal immune cells) and ex vivo (retinal explants) diabetic retinopathy-related inflammatory models, confirm its anti-inflammatory potential by downregulating key pro-inflammatory cytokines, activating the heme oxygenase-1 and reducing reactive gliosis.