Molecular targets in proliferative vitreoretinopathy: rethinking prevention, treatment and drug delivery after rhegmatogenous retinal detachment

INTRODUCTION: Proliferative vitreoretinopathy (PVR) is the leading cause of surgical failure after rhegmatogenous retinal detachment repair and the principal indication for repeat vitreoretinal surgery, yet four decades of mechanistic research have not produced an effective pharmacological adjunct. This review reexamines why, and asks how prevention, treatment and drug delivery might be reframed. AREAS COVERED: This narrative expert review conceptualizes PVR as a temporally evolving, overlapping fibro-inflammatory continuum spanning inflammation and chemotaxis, retinal pigment epithelial activation and epithelial-mesenchymal transition, proliferation, extracellular matrix deposition, membrane contraction and neurodegeneration. Informed by the current literature and the authors' experience, we appraise the key cellular drivers, the agents tested or proposed (corticosteroids, antimetabolites, anti-VEGF, anti-fibrotics and RNA-based approaches), emerging biology (mechanobiology, senescence, exosomes, epigenetics and ferroptosis), and the pharmacokinetic barriers and delivery platforms that constrain translation in the vitrectomized and oil-filled eye. EXPERT OPINION: Repeated trial failure reflects not a single failed target but recurring problems of patient selection, disease timing, pharmacokinetic mismatch, biological redundancy and trial design. Progress will require biomarker-enriched prevention in high-risk eyes, stage-matched combination therapy, delivery systems suited to the vitrectomized eye, and adequately powered multicenter trials pairing high-quality surgery with appropriately timed pharmacology.