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<p>Gene therapy has made significant progress in ophthalmology in recent years, particularly through adeno-associated virus (AAV)-mediated delivery. Despite well-known advantages of AAV vectors, their restricted cargo capacity, immunogenicity, and the presence of neutralizing antibodies against commonly used serotypes limit their use and efficacy. To address these limitations, we developed viral/nonviral chimeric nanoparticles (ChNPs) consisting of AAV2 vectors encapsulated by a polyketal acid-degradable polymeric shell and further functionalized with hyaluronic acid (HA). Additionally, a scrambled siRNA was incorporated into the polymeric shell to enable a multimodal therapeutic approach. In vitro safety, transduction efficiency and siRNA internalization of ChNPSs was investigated in retinal cells followed by an in vivo safety assessment for intravitreal delivery in rats. Characterization of ChNPs confirmed successful functionalization with HA, which resulted in improved size and uniformity as well as enhanced transduction efficiency in retinal cells when compared to HA-free ChNPs. Moreover, HA coating improved biocompatibility by maintaining retinal cells’ viability when incubated with ChNPs and allowed efficient siRNA internalization. A comprehensive in vivo assessment demonstrated that both HA-conjugated and HA-free ChNPs preserved retinal function, integrity, and morphology. Furthermore, the intraocular pressure and retinal thickness was not affected by ChNPs, confirming their safety for intravitreal delivery. Therefore, ChNPs coated with HA represent a promising alternative to overcome challenges with the most widely employed AAV vector in ocular gene delivery. Our findings support the potential for intravitreal administration of ChNPs and in multimodal gene expression/silencing strategies.</p>

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Assessment of AAV/polyketal chimeric nanoparticles for ocular gene transduction using an animal model

  • 期刊论文

  • 发表日期：

    2025年10月21日

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  • Brenda Fernanda Moreira Castro,
  • Margaret Lugin,
  • Maria Carolina Andrade Guerra,
  • Marina França Dias,
  • Rebecca T. Lee,
  • Armando Silva-Cunha,
  • Young Jik Kwon,
  • Silvia Ligório Fialho

摘要

Gene therapy has made significant progress in ophthalmology in recent years, particularly through adeno-associated virus (AAV)-mediated delivery. Despite well-known advantages of AAV vectors, their restricted cargo capacity, immunogenicity, and the presence of neutralizing antibodies against commonly used serotypes limit their use and efficacy. To address these limitations, we developed viral/nonviral chimeric nanoparticles (ChNPs) consisting of AAV2 vectors encapsulated by a polyketal acid-degradable polymeric shell and further functionalized with hyaluronic acid (HA). Additionally, a scrambled siRNA was incorporated into the polymeric shell to enable a multimodal therapeutic approach. In vitro safety, transduction efficiency and siRNA internalization of ChNPSs was investigated in retinal cells followed by an in vivo safety assessment for intravitreal delivery in rats. Characterization of ChNPs confirmed successful functionalization with HA, which resulted in improved size and uniformity as well as enhanced transduction efficiency in retinal cells when compared to HA-free ChNPs. Moreover, HA coating improved biocompatibility by maintaining retinal cells’ viability when incubated with ChNPs and allowed efficient siRNA internalization. A comprehensive in vivo assessment demonstrated that both HA-conjugated and HA-free ChNPs preserved retinal function, integrity, and morphology. Furthermore, the intraocular pressure and retinal thickness was not affected by ChNPs, confirming their safety for intravitreal delivery. Therefore, ChNPs coated with HA represent a promising alternative to overcome challenges with the most widely employed AAV vector in ocular gene delivery. Our findings support the potential for intravitreal administration of ChNPs and in multimodal gene expression/silencing strategies.