iRGD and TAT co-modified PEG-PLGA nanoparticles for topical ocular delivery of panax notoginseng saponins: A novel therapeutic strategy for diabetic retinopathy

Diabetic retinopathy (DR), a progressive microvascular-neurodegenerative disorder of the retina, is the leading cause of irreversible blindness in adults, for which there is no definitive treatment. Panax notoginseng saponins (PNS) and their bioactive components ginsenoside Rg1 (GRg1) and ginsenoside Rb1 (GRb1) have tremendous therapeutic potential in alleviating retinal damage via eye drops. However, the efficacy of conventional eye drops is severely constrained by the biological barriers of the eye, such as poor corneal penetration and inadequate posterior segment delivery. To overcome these challenges, this study designed a co-modified nanoparticles (NPs) delivery system by conjugating PEG-PLGA NPs with iRGD (an integrin-targeting peptide) and TAT (a cell-penetrating peptide). Three types of optimized formulations were developed: (1) 5% iRGD-5% TAT co-modified PNS@PEG-PLGA NPs, (2) 10% iRGD-5% TAT co-modified GRg1@PEG-PLGA NPs and (3) 10% iRGD-5% TAT co-modified GRb1@PEG-PLGA NPs. Comprehensive characterization revealed that these NPs exhibited uniform spherical morphology, nanoscale particle size, high encapsulation efficiency, superior drug loading capacity, and significant sustained release profiles. In vivo and in vitro experiments demonstrated that the 5% iRGD-5% TAT co-modified PNS@PEG-PLGA NPs, 10% iRGD-5% TAT co-modified GRg1@PEG-PLGA NPs, and 10% iRGD-5% TAT co-modified GRb1@PEG-PLGA NPs exhibited excellent ocular biocompatibility, and they could significantly enhance the corneal penetration, elevate aqueous humor drug concentrations, increase the amount of ocular tissue distribution, thus markedly improve the therapeutic efficacy in DR models compared to free APIs. In conclusion, the iRGD and TAT co-modified PEG-PLGA NPs delivery system is a topical ocular delivery system with high bioavailability, which provides a novel, safe, and effective therapeutic strategy for the treatment of DR.