RORα, short for retinoic acid receptor-related orphan receptor alpha, is a transcription factor that senses cholesterol levels and switches genes on or off in response. Genetic variants of the RORA gene have previously been associated with increased susceptibility to both the dry and neovascular forms of AMD in humans, and earlier work from the same group showed that RORα deficiency worsens laser-induced choroidal neovascularization in young mice. What remained unclear was exactly how the receptor influences the immune cells that swarm into the aging retina and whether its effects on fat metabolism and inflammation were two sides of the same coin. The new study set out to answer that question using two complementary mouse models: the spontaneous Staggerer mutant (Rora sg/sg), which lacks functional RORα throughout the body, and a myeloid-specific knockout (Rora fl/fl;LysMCre) in which the receptor is deleted only in macrophages and related immune cells.

The results were striking. As the Staggerer mice aged, they developed increasing numbers of abnormal whitish-yellow fundus lesions that resemble the drusen and deposits seen in human AMD patients, with more than a fivefold increase in lesion number by nine months of age. Retinal cross-sections revealed subretinal deposits, focal disruption of the retinal pigment epithelium, and sloughed RPE cells. Critically, the subretinal space of these mice, which in healthy eyes is normally kept free of immune cells by immunosuppressive factors secreted by the RPE, became crowded with CD11b- and IBA1-positive microglia and macrophages. The counts were more than double those of age-matched controls, and the accumulated immune cells were visibly bloated with neutral lipids, stained with a fluorescent lipid probe called LipidSpot 610. The number of these lipid-laden cells correlated with the density of fundus lesions, suggesting a causal relationship between immune cell fat overload and the visible pathology.

When the researchers induced choroidal neovascularization with laser photocoagulation in aged mice, the Staggerer animals fared far worse than controls. Their CNV lesions were significantly larger, surrounded by expanded zones of IBA1-positive macrophages and microglia, and far leakier on fluorescein angiography. While roughly 43 percent of lesions in wild-type aged mice showed only mild grade 1 hyperfluorescence and none reached the pathologically significant grade 2B, the RORα-deficient mice showed a much higher proportion of severely leaking lesions. Even outside the laser sites, the microglia of deficient mice displayed an activated, amoeboid morphology, with enlarged cell bodies, fewer branches, and shorter processes, the classic signature of inflammatory rather than surveillance-mode immune cells.

To prove that these effects stemmed from the immune cells themselves rather than some other tissue, the team turned to the myeloid-specific knockout. Deleting RORα only in the myeloid lineage reproduced the key findings: more fundus lesions at six, twelve, and beyond twelve months of age, larger lesion areas, increased subretinal accumulation of activated microglia, and elevated lipid droplet formation in immune cells of both young and aged animals. Laser-induced CNV lesions were larger in these mice as well, with 84 percent graded as leaky compared with 41 percent in floxed controls, and ex vivo choroidal explants from the knockout mice sprouted significantly more vessels, pointing to a pro-angiogenic shift driven by macrophages rather than by the vascular endothelium directly.

The mechanistic heart of the paper lies in what RORα does to PPARγ, a master regulator of fat uptake and storage. In RORα-deficient macrophages, retinas, and RPE/choroid tissue, Pparg mRNA and PPARγ protein were substantially upregulated, roughly doubling at the protein level. Chromatin immunoprecipitation experiments showed that RORα physically binds to a specific response element in the Pparg promoter, indicating that under normal conditions the receptor directly represses this lipogenic gene. When RORα is absent or pharmacologically inhibited with inverse agonists such as SR3335 and SR1001, PPARγ expression surges, lipid droplet formation increases roughly threefold, and macrophages take up more low-density lipoprotein. Exposure to 7-ketocholesterol, an oxidized cholesterol product that is a major component of drusen, further exaggerated lipid accumulation in the deficient cells, highlighting their heightened vulnerability to the very molecules that pile up in AMD eyes.

The lipid overload was not benign. RORα-deficient macrophages, retinas, and RPE/choroid samples showed elevated levels of the pro-inflammatory cytokines TNFα, IL-6, and IL-1β, along with reduced anti-inflammatory IL-10, and increased activation of NF-κB, the central inflammatory signaling pathway implicated in AMD. The deficient immune cells also lost expression of two migratory receptors, CX3CR1 and CD47, which are essential for macrophages and microglia to exit the subretinal space once their cleanup work is done. CD47 in particular is a known AMD risk factor that declines with age in humans. With these exit routes downregulated, the cells became trapped, proliferated more actively, migrated more aggressively in transwell assays, and produced more angiogenic factors including VEGF-A, VEGF-D, and angiopoietin-2. Conditioned medium from lipid-laden macrophages even stimulated the proliferation of human choroidal endothelial cells in culture, providing a direct functional link between macrophage fat overload and new blood vessel growth.

Perhaps most importantly for patients, the pathway proved druggable, at least in mice. When the researchers treated myeloid-specific knockout animals with T0070907, a selective PPARγ antagonist, before and during laser-induced CNV, lesion size shrank significantly, lipid droplet accumulation in retinal macrophages dropped markedly, and retinal expression of TNFα and IL-6 fell. This demonstrates that PPARγ acts as a key downstream effector of RORα signaling and that blocking it can partially reverse the damage caused by losing the receptor. In other words, the RORα–PPARγ axis offers a concrete therapeutic target: restoring RORα function or damping PPARγ activity could, in principle, restore lipid balance in retinal immune cells and cool the chronic inflammation that fuels neovascularization.

The findings arrive at a moment of growing translational momentum for RORα biology. A recent study showed that RORA-expressing gene therapy rescued retinal degeneration in a mouse model of Stargardt disease and dry AMD, and clinical trials evaluating RORA as a gene modifier therapy are currently underway for those conditions. The new work extends the receptor’s relevance to the wet, neovascular form of the disease and pinpoints the myeloid cell as the critical cellular mediator. There are caveats: the LysMCre system does not exclusively target microglia and shows incomplete recombination in that population, so the results reflect deletion in LysM-expressing myeloid cells broadly, and the human genetic association data for RORA and AMD risk have not been extensively updated by more recent studies. Still, the convergence of mouse genetics, pharmacology, chromatin biology, and human genetic association makes a compelling case that RORα sits at the junction of lipid metabolism and immune regulation in the aging retina.

What emerges is a coherent model of AMD pathogenesis in which a single nuclear receptor orchestrates an entire disease program. Under normal conditions, active RORα signaling keeps PPARγ in check, maintains lipid homeostasis in microglia and macrophages, supports the expression of migratory receptors that allow immune cells to leave the subretinal space, and restrains inflammatory cytokine production. When RORα is lost, whether through genetic variation, aging-related dysfunction, or the flood of oxidized cholesterol that characterizes the AMD eye, the system flips: PPARγ rises, immune cells gorge on lipids and become trapped, NF-κB-driven inflammation intensifies, and pro-angiogenic signals recruit the abnormal choroidal vessels that destroy central vision. If future therapies can reengage this axis in human patients, they may finally address one of the deepest roots of a disease that currently can only be managed, not prevented, at its immunometabolic source.

Subject of Research: Role of the nuclear receptor RORα in myeloid cell lipid metabolism, subretinal inflammation, and choroidal neovascularization in age-related macular degeneration

Article Title: Myeloid deficiency of RORα exacerbates lipid dysregulation and laser-induced choroidal neovascularization

Article References: Kushwah, N., Liu, C.-H., Bora, K., Maurya, M., Pavlovich, M. C., Fu, Z., Kamenecka, T. M., Sun, Y., Solt, L. A., & Chen, J. (2026). Myeloid deficiency of RORα exacerbates lipid dysregulation and laser-induced choroidal neovascularization. Angiogenesis, 29(4), Article 73. https://doi.org/10.1007/s10456-026-10092-2

Image Credits: AI Generated

DOI: 10.1007/s10456-026-10092-2

Keywords: RORα, age-related macular degeneration, choroidal neovascularization, macrophages, microglia, PPARγ, lipid accumulation, inflammation, nuclear receptor, retina, drusen, NF-κB

The clinical motivation is stark. Myopia has become one of the fastest-growing public health problems in the world, particularly among children and adolescents, and it is far more than a simple refractive error that glasses can fix. Progressive myopia involves excessive elongation of the eyeball, driven by a cascade that begins in the retina and ends in structural weakening of the sclera, the tough outer coat of the eye. Genetic susceptibility combines with environmental pressures such as prolonged near work, insufficient outdoor light exposure and abnormal retinal defocus to alter retinal neurotransmission, including dopamine signalling. These changes disturb the release of growth modulators such as retinoic acid, TGF-β and insulin-like growth factor, which in turn destabilize the balance of collagen synthesis and degradation in the sclera, mediated by matrix metalloproteinases and activated fibroblasts. The result is a thinner, softer sclera that deforms under normal intraocular pressure, stretching the eye axially and predisposing patients to retinal detachment, myopic macular degeneration and optic neuropathy.

SENGs attack this problem from a fundamentally different angle than conventional optical correction. The review divides the technology into two complementary classes. Piezoelectric nanogenerators, or PENGs, exploit materials such as zinc oxide nanowires, barium titanate nanoparticles and piezoelectric polymers like PVDF and its copolymer P(VDF-TrFE), in which mechanical deformation shifts internal charge distributions and creates a piezoelectric potential that drives current through an external circuit. Triboelectric nanogenerators, or TENGs, instead harvest charge generated when two materials with different electron affinities make contact and separate, an effect amplified by electrostatic induction. PENGs deliver moderate voltages with relatively higher current and suit implantable stimulation scenarios, while TENGs produce high open-circuit voltages at very low currents and excel in flexible wearable formats such as contact lenses and eyeglass-mounted sensors. Both operate comfortably within the mechanical regime of the eye, where a normal blink imposes roughly 2 to 5 kilopascals of pressure and forceful blinking can exceed 10 kilopascals.

The most striking preclinical demonstrations come from device prototypes that translate these physics into therapy. One electro-driven drug delivery system integrates barium titanate nanoparticles coated with atropine into an orthokeratology lens. When the wearer closes their eyes, eyelid pressure triggers the piezoelectric effect, generating transient microvoltages that are proposed to perturb the interfacial electrostatic equilibrium of the nanoparticles and promote atropine desorption. Release rates reach approximately 80 percent within 12 hours, with more release accumulating the longer the eyes remain closed, effectively synchronizing drug delivery with natural physiology. In guinea pig myopia models, this system achieved superior reversal of refractive error compared with atropine eye drops alone or combined lens-plus-drop regimens, increased choroidal blood flow velocity, and raised ocular tissue drug concentrations more than twenty-fold above blood levels without detectable systemic toxicity or ocular surface irritation.

Electrical stimulation itself may also remodel the diseased sclera. Inspired by the electrocyte discharge of electric eels, researchers developed a biomimetic piezoelectric patch called BPP@PVDF, made by spin-coating a piezoelectric PVDF membrane onto a bovine pericardium scaffold. Under physiological ocular deformation, the patch generates self-powered microcurrents that were associated with increased scleral fibroblast proliferation and type I collagen synthesis. In rabbit models of lens-induced myopia, eyes receiving the patch showed over 40 percent less axial elongation than sham-operated controls, along with denser and more regularly organized collagen fibers, 20 to 30 percent greater scleral tensile strength and no abnormalities in intraocular pressure, retina or cornea. The authors are careful to stress, however, that the intracellular signaling pathways connecting generated electricity to fibroblast activation remain incompletely defined, and long-term risks such as pathological fibrosis have not been systematically excluded.

Drug delivery to the back of the eye is a second major frontier. Intravitreal injections carry infection and retinal detachment risks, while non-invasive routes typically achieve delivery efficiencies below 5 percent. A wearable electric switch system comprising an electrically driven drug delivery lens and a flexible square-wave generator addresses this bottleneck by using electrical stimulation to transiently open junctions between retinal pigment epithelial cells, reducing resistance along the sclerochoroidal-retinal pathway. The system delivered immunoglobulin G with 14 percent efficiency, approaching the 16 percent achieved by intravitreal injection, enhanced macromolecular penetration three- to five-fold in rabbit eyes and worked across monoclonal antibodies, DNA origami and extracellular vesicles, with adjustable waveform parameters providing a controllable safety window.

The same physics also supports closed-loop sensing. Triboelectric sensors mounted on skin or eyeglasses can distinguish voluntary from involuntary blinks, decode eye movements in eight directions with micrometer spatial resolution, and monitor intraocular pressure with sensitivities of about 1.28 megahertz per millimeter of mercury. A wireless therapeutic contact lens platform integrating sensing, wireless communication and iontophoretic drug delivery has maintained stable intraocular pressure readings for up to two months in rabbits while delivering anti-glaucoma medication on demand. Combined with machine learning, such self-powered sensors could feed adaptive algorithms that adjust stimulation and drug-release parameters in real time, forming the basis of an intelligent feedback loop between the eye, external computation and therapy. The review notes that tellurium nanowire retinal nanoprostheses and the clinically validated PRIMA photovoltaic implant, while not energy harvesters themselves, provide powerful engineering templates for wireless neural interfacing and long-term biointegration that future SENG platforms can borrow.

Formidable challenges separate the laboratory from the clinic. The eye is a hostile environment for electronics: tear fluid shields surface charges, millions of blinks per year accelerate mechanical fatigue and delamination, and materials such as zinc oxide can dissolve and release cytotoxic ions, while lead-based piezoceramics pose obvious toxicity concerns that push designers toward lead-free alternatives like barium titanate and biodegradable polymers such as PLGA. A fundamental ‘power gap’ also persists, since blink-driven generators produce transient bursts rather than the continuous, tightly regulated currents needed for reliable neuromodulation, and patients with dry eye or impaired ocular motility generate too little biomechanical energy for dependable therapy. Hybrid devices that pair nanogenerators with miniature supercapacitors or thin-film batteries could buffer this variability. Regulatory pathways add another layer of complexity, because multifunctional platforms combining stimulation, drug delivery, biosensing and artificial intelligence will likely be classified as combination products requiring coordinated review of electrical safety, pharmacology, software reliability and cybersecurity. Pediatric use, the population that most needs myopia control, raises additional ethical and developmental concerns that will demand adult safety data first.

Even so, the trajectory is clear. Ophthalmic biomaterials are evolving from passive structural supports into dynamic, intelligent systems that sense, respond and adapt. By harvesting the eye’s own motion to power stimulation, drug release and continuous monitoring, self-generated electricity nanogenerators sketch a future in which myopia is actively managed as the progressive neurovascular disease it truly is, rather than passively corrected with lenses. If materials scientists, neuroscientists and clinicians can close the remaining gaps in energy stability, chronic biocompatibility and validated dosing, the review concludes, blinking may one day do far more than keep the eye wet. It could power the therapy that saves a child’s sight.

Subject of Research: Self-powered bioelectronic nanogenerators for myopia treatment and vision restoration

Article Title: Bioelectronic interfaces for restoring vision pathways

Article References: Wang, T., Zhao, B., Du, Y., Wu, S., Jiang, Y., Li, J., Miao, Y.-B., & Shi, Y. (2026). Bioelectronic interfaces for restoring vision pathways. Materials Today Bio, 40, Article 103652. https://doi.org/10.1016/j.mtbio.2026.103652

Image Credits: AI Generated

DOI: 10.1016/j.mtbio.2026.103652

Keywords: myopia, nanogenerators, triboelectric, piezoelectric, bioelectronics, drug delivery, retina, sclera, biomaterials, energy harvesting, contact lenses, neuromodulation