Vision has profound influence on the quality of life. Up to now, the number of visually impaired patients worldwide is about 1.3 billion, of which 36 million are blind. Chronic posterior ocular diseases are the causal factors for severe vision impairment and even blindness, including hereditary retinopathy, retinoblastoma, age-related macular degeneration and diabetic retinopathy. Gene therapy is bringing hope for those patients with irreversible vision loss due to retina degeneration. However, it is difficult for those hydrophilic macromolecules to enter the eye due to various ocular absorption barriers. As a result, there are nothing but intraocular injection for posterior ocular delivery of the approved gene drugs. Unfortunately, repetitive intraocular injection is usually with low patient compliance for the inevitable side effects, e.g. endophthalmitis, retinal detachment and intraocular hemorrhage.
To change the status quo, Prof. Gang Wei’s group endeavors to achieve noninvasive intraocular gene delivery. Previously, using cationic polymers to compact gene with surface modified by ocular permeation peptides, Prof. Wei’s group has designed a series of noninvasive intraocular gene delivery system with encouraging efficiency. Recently, inspired by the octopus, Prof. Wei’s group designed a kind of flexible multivalent penetratin (MVP) as gene vectors, using multi-arm polyethylene glycol (PEG) as a core and conjugating ocular permeation peptide penetratin at each end of PEG arms. Through a facile mixing process, cationic MVP could self-assemble with anionic nucleic acids (antisense oligonucleotides or siRNA) to form polyplexes smaller than 100 nm. Notably, like preying octopus, part of penetratin tentacles could compact and carry gene, while others stretch out to implement ocular permeation. More importantly, those topically instilled polyplexes could efficiently inhibit protein expression of intraocular retinoblastoma, mainly through a non-corneal pathway, which provided a safe and efficient strategy for noninvasive intraocular gene therapy. Besides, compared to widely-used cationic liposomes in biological research, MVP had better biocompatibility, and could facilely form stable polyplexes with gene and achieve satisfying ocular absorption, exhibiting the potential to be a universal gene vector and facilitate clinical translation of gene therapy.
This work has been published in Nano Letters recently with the title of “Octopus-like flexible vector for noninvasive intraocular delivery of short interfering nucleic acids”. The corresponding author was Prof. Gang Wei in School of Pharmacy, Fudan University, and the first author was Ph.D candidate Kuan Jiang. This work received financial support from the National Natural Science Foundation of China.
Flexible octopus-like multivalent penetratin self-assembled with short interfering nucleic acids to form polyplexes, and exhibited obvious distribution in posterior ocular segment (retina) mainly through the non-corneal pathway.
