Regulated cell death-targeted ocular nanomedicine.

The pathological mechanism of ocular disorders is closely related to dysregulated proliferation or death of ocular cells. Regulated cell death (RCD) is a form of cell death controlled by specific signaling pathways. Diverse types of RCD, such as apoptosis, ferroptosis, autophagy, pyroptosis, and necroptosis, are prevalent in many eye diseases, while the modulation of RCD can alter ocular cell fate and improve disease progression. The pharmacological inducers and inhibitors of RCD have been developed as an emerging approach for ocular therapy. However, the complex ocular anatomy and barriers hinder the efficient use of RCD modulating drugs. Nanomedicine has emerged as a versatile tool in ophthalmic applications for its advanced properties in penetrating ocular barriers, preventing burst effects and rapid inactivation, enabling targeted and controlled release, and facilitating co-delivery of therapeutic agents. Similarly, nanomedicine has been widely explored for its potential in modulating RCD to treat ocular disorders. This review provides a comprehensive overview of the mechanistic roles of five major forms of RCD in eye diseases, summarizes the application of ocular nanomedicine that targets the RCD pathways, and discusses the future prospects of RCD-targeted ocular nanomedicine. It is expected that the elaborately designed RCD-targeted nanomedicine for ocular therapy will play an indispensable role for the establishment of next-generation ocular theranostic nanoplatforms. STATEMENT OF SIGNIFICANCE: Regulated cell death (RCD) significantly manipulates ocular cell fate and is a key driver in the progression of several vision-threatening diseases. However, the complex ocular structures limit the effective use of RCD-regulating therapies. Nanomedicine has emerged as a promising tool to overcome the limitations of the ocular anatomy and precisely modulate RCD, offering new avenues for therapeutic intervention in ocular diseases. In this review, we summarize the mechanistic role of RCD in the pathogenesis of ocular disorders, review current ocular nanomedicines that target the RCD pathway, and discuss the future prospects of RCD-targeted ocular nanomedicine. We aim to provide insights into the potential of targeted nanomedicine in advancing the therapeutics of ocular disorders.