Semen-Derived Exosomes Eye Drops to Treat Retinoblastoma

By Pooja Toshniwal PahariaReviewed by Lauren HardakerApr 8 2026

In a recent study published in Science Advances, researchers developed a novel, non-invasive strategy for therapeutic delivery to the posterior region of the eyes using semen-derived extracellular vesicles (SEVs). Drawing inspiration from their natural biological role, the team showed that SEVs can safely and reversibly open tight junctions in the ocular barrier, enabling efficient cargo penetration.

By engineering SEV-based eye drops to target retinoblastoma cells, the approach demonstrated potent anti-tumor effects while preserving retinal function, offering a promising new avenue for treating difficult-to-reach posterior eye diseases.

Noninvasive Retinal Drug Delivery Remains a Major Challenge

Treating diseases of the eye’s posterior segment remains challenging. Current approaches often rely on invasive procedures that can damage delicate ocular structures or cause systemic side effects. This is particularly evident in retinoblastoma, the most common intraocular cancer in children. To treat these tumors, therapies such as injections, radiotherapy, or even eye removal may be required.

Exosomes are small extracellular vesicles known for their good biocompatibility, minimal immune activation, and capacity to traverse biological barriers. These properties make them promising drug delivery vehicles. However, their potential for non-invasive ocular delivery remains underexplored, with SEVs offering a uniquely adapted, barrier-penetrating alternative.

Bioengineered SEV Eye Drops Combine Targeting and Nanozymes

In the present study, researchers designed and tested a biomimetic eye drop system, FA-SEVs@CMG. The system comprised SEVs modified using folic acid and loaded with a multifunctional nanozyme (CMG). The nanoenzyme contains carbon dots (CDs), glucose oxidase (GOx), and manganese dioxide (MnO₂). The team first synthesized and characterized the carbon dots, confirming their structure, stability, and near-infrared fluorescence for real-time tracking. Next, they isolated SEVs from porcine semen and verified their purity, size, and exosomal markers using microscopy and protein analysis.

To evaluate ocular delivery, the investigators incorporated fluorescent carbon dots into SEVs and assessed their permeability across corneal models, human corneal epithelial cell monolayers, and in vivo animal models, including mice and rabbits, and compared them with multiple controls. They also examined SEV interactions with tight junctions in corneal epithelial cells.

The researchers assessed barrier integrity using transepithelial electrical resistance (TEER). Proteomic analyses and targeted experiments helped identify key proteins and signaling pathways involved in barrier modulation, including the role of epidermal growth factor (EGF) in regulating barrier permeability.

After confirming efficient ocular penetration, the researchers engineered the final FA-SEVs@CMG formulation and tested its targeting and therapeutic effects in retinoblastoma cell lines and tumor-bearing mouse models. They evaluated drug accumulation, oxidative stress, and downstream cellular responses, including autophagy and apoptosis.

Lastly, they conducted safety assessments, including pathogen screening of porcine samples, repeated-dose studies in mice and rabbits, and in vivo ocular imaging, to assess potential toxicity and long-term effects.

SEVs Outperform Conventional Carriers in Retinal Penetration

The SEVs were more effective than conventional exosomes and liposomal carriers in delivering the study cargo to the back of the eye. In both mouse and rabbit models, SEVs showed significantly higher ocular penetration, with rapid accumulation in the retina and choroid within six hours of topical administration. This enhanced delivery was driven by the ability to transiently and reversibly open epithelial tight junctions, allowing efficient passage without long-term structural damage.

Importantly, SEVs exploited dual corneal and conjunctival pathways, enabling a more comprehensive “omnidirectional” route to the fundus, with the conjunctival-scleral pathway identified as the dominant route.

Mechanistic analyses revealed that this effect is driven by EGF carried within SEVs, which activate the EGFR–Src–MLCK signaling cascade that regulates tight junction permeability. Blocking EGF or EGFR significantly reduced ocular penetration, confirming its central role.

Therapeutically, the engineered system showed strong anti-tumor efficacy. In retinoblastoma cell models, it induced high levels of oxidative stress, triggering linked processes including ferroptosis, mitochondrial dysfunction, autophagy, and apoptosis, with autophagy shifting from a protective response to a pro-death mechanism that ultimately led to tumor cell self-destruction.

In vivo, treated mice exhibited substantial tumor suppression, with tumor burden reduced to low residual levels (~2% of control in the optimized formulation) and preserved retinal structure and function.

Notably, the folic acid–targeted formulation (FA-SEVs@CMG) also enabled real-time fluorescence-based tracking of tumor progression by selectively accumulating in tumor tissue. Safety evaluations across mice and rabbits confirmed minimal toxicity, no significant inflammation, and signals largely cleared within 24 hours. Together, these findings highlight SEVs as a promising preclinical platform for non-invasive ocular drug delivery.

Bioinspired Platform Offers New Path for Ocular Diseases

The study introduces the first semen-derived extracellular vesicle–based platform for non-invasive drug delivery to the posterior segment of the eye, addressing a major unmet need in ocular therapeutics. By enabling dual-pathway penetration and targeted tumor delivery, the engineered eye drops effectively suppressed retinoblastoma growth while preserving retinal function and allowing real-time disease monitoring. Beyond cancer, this approach may inform future strategies for treating a range of vision-threatening retinal disorders.

However, translating SEVs into clinical practice will require overcoming key challenges, including large-scale manufacturing, standardization, and biosafety concerns. Future research should focus on refining production under regulatory standards and exploring bioinspired alternatives, such as EGF-based nanocarriers. Together, these strategies could accelerate the development of safer, non-invasive therapies for retinal diseases and ocular cancers.

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Journal Reference

Zhao, J. et al. (2026). Harnessing semen-derived exosomes for noninvasive fundus drug delivery: A paradigm for exosome-based ocular fundus therapeutics. Science Advances. DOI: 10.1126/sciadv.adw7275. https://www.science.org/doi/10.1126/sciadv.adw7275