Intranasally delivered fucoidan nanozyme-decorated photosynthetic Chlamydomonas regulates vascular pathology and hypoxia in diabetes-associated retinal microvascular dysfunction.

Diabetic retinopathy (DR) is a leading cause of vision loss and is strongly associated with microvascular pathology and retinal hypoxia. Here, we report an intranasally delivered microalgae drug delivery system, Chlamydomonas@Pro-Fu-PEDOT nanozymes (CHL@Pro-Fu-PEDOT-NZs), engineered to target retinal injury. Under 660-nm red-light irradiation, the platform exploits the photosynthetic activity of Chlamydomonas to generate bioelectric cues and therapeutic gases (O2), thereby alleviating hypoxia and reducing vascularization. Fucoidan functionalization further confers P-selectin-mediated vascular addressing, enabling lesion-focused delivery and regulation of hypoxia-driven vascular responses through photosynthesis-inspired gas generation and bioelectrical modulation. In vitro, CHL@Pro-Fu-PEDOT-NZs exhibited excellent biocompatibility and protected retinal ganglion cells from oxidative and inflammatory injury. In a streptozotocin (STZ)-induced DR mouse model, intranasal delivery mitigated pathological retinal responses, as evidenced by reduced VEGF and HIF-1α expression, and yielded measurable improvements in visual behavior, without detectable systemic toxicity. Collectively, this multifunctional, noninvasive therapeutic platform offers strong potential for DR treatment by simultaneously addressing vascular dysfunction, and hypoxia.