Current diabetic retinopathy (DR) treatment involves blood glucose regulation combined with laser photocoagulation or intravitreal injection of vascular endothelial growth factor (VEGF) antibodies. However, due to the complex pathogenesis and cross-interference of multiple biochemical pathways, these interventions cannot block disease progression. Recognizing the critical role of the retinal microenvironment (RME) in DR, it is hypothesized that reshaping the RME by simultaneously inhibiting primary and secondary blood-retinal barrier (BRB) injury can attenuate DR. For this, a glucose-responsive hydrogel named Cu-PEI/siMyD88@GEMA-Con A (CSGC) is developed that effectively delivers Cu-PEI/siMyD88 nanoparticles (NPs) to the retinal pigment epithelium (RPE). The Cu-PEI NPs act as antioxidant enzymes, scavenging ROS and inhibiting RPE pyroptosis, ultimately blocking primary BRB injury by reducing microglial activation and Th1 differentiation. Simultaneously, MyD88 expression silence in combination with the Cu-PEI NPs decreases IL-18 production, synergistically reduces VEGF levels, and enhances tight junction proteins expression, thus blocking secondary BRB injury. In summary, via remodeling the RME, the CSGC hydrogel has the potential to disrupt the detrimental cycle of cross-interference between primary and secondary BRB injury, providing a promising therapeutic strategy for DR.

Department of Chemistry and Biochemistry Mendel University in Brno Brno CZ 61300 Czech Republic

Department of Ophthalmology Peking Union Medical College Hospital Chinese Academy of Medical Sciences Beijing 100730 P R China

Department of Pharmacy Tianjin Union Medical Center Nankai University Tianjin 300122 P R China

Key Laboratory of Ocular Fundus Diseases Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 P R China

Tianjin Key Laboratory of Drug Delivery and High Efficiency School of Pharmaceutical Science and Technology Tianjin University Tianjin 300072 P R China

See more in PubMed

Bourne R. R., Stevens G. A., White R. A., Smith J. L., Flaxman S. R., Price H., Jonas J. B., Keeffe J., Leasher J., Naidoo K., Pesudovs K., Resnikoff S., Taylor H. R., Vision Loss Expert Group , Lancet Glob. Health 2013, 1, e339. PubMed

a) Klaassen I., Van Noorden C. J., Schlingemann R. O., Prog. Retinal Eye Res. 2013, 34, 19; PubMed

b) Wang W., Lo A. C. Y., Int. J. Mol. Sci. 2018, 19, 1806. PubMed

Rodriguez M. L., Millan I., Ortega A. L., World J. Diabetes 2021, 12, 1442. PubMed PMC

Das A., McGuire P. G., Rangasamy S., Ophthalmology 2015, 122, 1375. PubMed

Zhang C.‐J., Jin Z.‐B., Curr. Med. 2023, 2, 4.

Murakami Y., Ishikawa K., Nakao S., Sonoda K. H., Prog. Retin. Eye. Res. 2020, 74, 100778. PubMed

a) Willermain F., Scifo L., Weber C., Caspers L., Perret J., Delporte C., Int. J. Mol. Sci. 2018, 19, 1056; PubMed PMC

b) Ramos H., Hernández C., Simó R., Simó‐Servat O., Int. J. Mol. Sci. 2023, 24, 8796. PubMed PMC

Kovoor E., Chauhan S. K., Hajrasouliha A., Surv. Ophthalmol. 2022, 67, 1563. PubMed PMC

Yang X., Yu X.‐W., Zhang D.‐D., Fan Z.‐G., Chin. Med. J. 2020, 133, 2586. PubMed PMC

Palenski T. L., Sorenson C. M., Sheibani N., Microvasc. Res. 2013, 89, 57. PubMed PMC

a) Erickson K. K., Sundstrom J. M., Antonetti D. A., Angiogenesis 2007, 10, 103; PubMed

b) Diaz‐Coranguez M., Ramos C., Antonetti D. A., Vision Res. 2017, 139, 123. PubMed PMC

a) Maslanik T., Mahaffey L., Tannura K., Beninson L., Greenwood B. N., Fleshner M., Brain Behav. Immun. 2013, 28, 54; PubMed

b) Savage C. D., Lopez‐Castejon G., Denes A., Brough D., Front. Immunol. 2012, 3, 288. PubMed PMC

Man S. M., Kanneganti T. D., Immunol. Rev. 2015, 265, 6. PubMed PMC

a) Liu J., Copland D. A., Theodoropoulou S., Chiu H. A., Barba M. D., Mak K. W., Mack M., Nicholson L. B., Dick A. D., Sci. Rep. 2016, 6, 20639; PubMed PMC

b) Gao J., Cui J. Z., To E., Cao S., Matsubara J. A., J. Neuroinflamm. 2018, 15, 15. PubMed PMC

Tarallo V., Hirano Y., Gelfand B. D., Dridi S., Kerur N., Kim Y., Cho W. G., Kaneko H., Fowler B. J., Bogdanovich S., Albuquerque R. J., Hauswirth W. W., Chiodo V. A., Kugel J. F., Goodrich J. A., Ponicsan S. L., Chaudhuri G., Murphy M. P., Dunaief J. L., Ambati B. K., Ogura Y., Yoo J. W., Lee D. K., Provost P., Hinton D. R., Nunez G., Baffi J. Z., Kleinman M. E., Ambati J., Cell 2012, 149, 847. PubMed PMC

Zhou R., Yazdi A. S., Menu P., Tschopp J., Nature 2011, 469, 221. PubMed

Rasoulinejad S. A., Karkhah A., Paniri A., Saleki K., Pirzadeh M., Nouri H. R., Immunopharmacol. Immunotoxicol. 2020, 42, 400. PubMed

Ozaki E., Campbell M., Doyle S. L., J. Inflamm. Res. 2015, 8, 15. PubMed PMC

Warner N., Nunez G., J. Immunol. 2013, 190, 3. PubMed

Liao Y. R., Li Z. J., Zeng P., Lan Y. Q., Biochem. Biophys. Res. Commun. 2017, 493, 1136. PubMed

a) Zhang X., Bao S., Lai D., Rapkins R. W., Gillies M. C., Diabetes 2008, 57, 1026; PubMed PMC

b) Zhang X., Zeng H., Bao S., Wang N., Gillies M. C., Cell Biosci. 2014, 4, 27. PubMed PMC

Pickup J. C., Hussain F., Evans N. D., Rolinski O. J., Birch D. J., Biosens. Bioelectron. 2005, 20, 2555. PubMed

Yui N., Supramolecular Design for Biological Applications, CRC Press, Boca Raton, FL USA, 2002.

Li H., Wang H., Wang F., Gu Q., Xu X., PLoS One 2011, 6, e23322. PubMed PMC

Ghassemifar R., Lai C. M., Rakoczy P. E., Cell Tissue Res. 2006, 323, 117. PubMed

a) Cho J. S., Kang J. H., Han I. H., Um J. Y., Lee H. M., Clin. Exp. Allergy 2013, 43, 1038; PubMed

b) Zhang R., Ai X., Duan Y., Xue M., He W., Wang C., Xu T., Xu M., Liu B., Li C., Wang Z., Zhang R., Wang G., Tian S., Liu H., Biomed. Pharmacother. 2017, 89, 660. PubMed

Ragelle H., Goncalves A., Kustermann S., Antonetti D. A., Jayagopal A., J. Ocul. Pharmacol. Ther. 2020, 36, 30. PubMed PMC

Nakahara T., Morita A., Yagasaki R., Mori A., Sakamoto K. J. B., Bulletin P., Biol. Pharm. Bull. 2017, 40, 2045. PubMed

Yasuda K., Nakanishi K., Tsutsui H., Int. J. Mol. Sci. 2019, 20, 649. PubMed PMC

Iyer S. S., He Q., Janczy J. R., Elliott E. I., Zhong Z., Olivier A. K., Sadler J. J., Knepper‐Adrian V., Han R., Qiao L., Eisenbarth S. C., Nauseef W. M., Cassel S. L., Sutterwala F. S., Immunity 2013, 39, 311. PubMed PMC

McKenzie B. A., Mamik M. K., Saito L. B., Boghozian R., Monaco M. C., Major E. O., Lu J. Q., Branton W. G., Power C., Proc. Nat. Acad. Sci. USA 2018, 115, E6065. PubMed PMC

Xi X., Yang Y., Ma J., Chen Q., Zeng Y., Li J., Chen L., Li Y., Biomed. Pharmacother. 2020, 125, 109924. PubMed

Kawanaka N., Taylor A. W., J. Neuroimmunol. 2011, 232, 17. PubMed PMC

Rathnasamy G., Foulds W. S., Ling E. A., Kaur C., Prog. Neurobiol. 2019, 173, 18. PubMed

Luo X. G., Chen S. D., Transl. Neurodegener. 2012, 1, 9. PubMed PMC

Spaide R. F., Koizumi H., Pozzoni M. C., Am. J. Ophthalmol. 2008, 146, 496. PubMed

Hsueh H. T., Kim Y. C., Pitha I., Shin M. D., Berlinicke C. A., Chou R. T., Kimball E., Schaub J., Quillen S., Leo K. T., Han H., Xiao A., Kim Y., Appell M., Rai U., Kwon H., Kolodziejski P., Ogunnaike L., Anders N. M., Hemingway A., Jefferys J. L., Date A. A., Eberhart C., Johnson T. V., Quigley H. A., Zack D. J., Hanes J., Ensign L. M., Pharmaceutics 2021, 13, 647. PubMed PMC

Hsueh H. T., Chou R. T., Rai U., Liyanage W., Kim Y. C., Appell M. B., Pejavar J., Leo K. T., Davison C., Kolodziejski P., Mozzer A., Kwon H., Sista M., Anders N. M., Hemingway A., Rompicharla S. V. K., Edwards M., Pitha I., Hanes J., Cummings M. P., Ensign L. M., Nat. Commun. 2023, 14, 2509. PubMed PMC