By Dr. Andrew French PhD, Dr. Richard Boyd PhD, Prof. Alice Pébay PhD, Prof. Alan Trounson PhD.
As published in Drug Discovery World, Fall 2026, pages 12-14
Towards a new therapeutic paradigm targeting a-synuclein pathology, neuroinflammation and neuronal vulnerability.
This article explores emerging research into NK cell-derived extracellular vesicles (NK-EVs) as a potential therapeutic platform for neurodegenerative disease. Evinco Therapeutics is developing NK-EV- based approaches targeting neurological disorders.
Neurodegenerative diseases represent one of the greatest unmet challenges in modern medicine. Despite decades of research, current therapies remain largely symptomatic without addressing the biological processes driving disease progression. As populations age globally, the burden of disorders such as Parkinson’s disease (PD) continues to rise, highlighting the urgent need for disease-modifying interventions.
Parkinson’s disease: pathogenesis and therapeutic need
From 2021 to 2050, the global number of PD cases is projected to increase by 112%, reaching 25.2 million in 2050[i]. PD is a progressive neurodegenerative disorder characterised by the selective loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the consequent depletion of dopamine in the striatum.
Clinically, PD is characterised by the cardinal motor features of bradykinesia, rigidity, resting tremor and postural instability. A broad range of non‑motor symptoms often precede or accompany the motor manifestations, including hyposmia, constipation, rapid eye movement sleep behaviour disorder, mood disturbances, autonomic dysfunction, and in later stages, cognitive decline.
While genetic factors including mutations in SNCA, LRRK2, PINK1, PRKN and GBA1 contribute to risk[ii], most Parkinson’s cases are sporadic and arise through interactions between ageing-related cellular-related cellular vulnerability, environmental exposures and immune disfunction.[iii]
Current treatments remain largely symptomatic. Levodopa, dopamine agonists and monoamine oxidase‑B inhibitors improve dopaminergic signalling, while neuromodulatory interventions such as deep brain stimulation provide substantial benefit in selected patients.[iv] However, these approaches do not prevent the progressive degeneration of nigrostriatal neurons. There is therefore a need for therapies that target the underlying disease process rather than its clinical consequences alone.[v]
Alpha-synuclein: The catalyst of neuroinflammation
Alpha‑synuclein (α -syn) is a small presynaptic protein involved in synaptic vesicle dynamics and neurotransmitter release, including dopaminergic neurotransmission. Under physiological conditions, α -syn is tightly regulated. However, in pathological conditions, α -syn can misfold and assemble into oligomeric and fibrillar species. Aggregated α -syn is a major component of Lewy bodies, the characteristic pathological inclusions associated with PD. However, the relative contribution of different α-syn species to neuronal toxicity remains uncertain.[vi]
Pathological α-syn can disrupt synaptic function, mitochondrial activity, membrane integrity and intracellular protein clearance pathways. Misfolded species can also move between cells and promote further aggregation, a potential mechanism for the spread of pathology. Together these effects contribute to neuronal vulnerability.[vii]
Microglia and astrocytes can contribute to the uptake and degradation of extracellular α-syn. However, persistent exposure to misfolded proteins, cellular debris and inflammatory signals can promote glial activation, leading to glial release of cytokines, reactive oxygen species and complement components that amplify neuronal stress.[viii] Age-associated reductions in proteostasis and immune function can also further impair the removal of pathological proteins and favour chronic neuroinflammation.[ix]
Current disease-modifying approaches
Given the role of α-syn accumulation in PD pathology, therapeutic strategies have focused on reducing pathological α-syn species, preventing aggregation and limiting spread. Passive immunotherapies using monoclonal antibodies have shown limited success, with Cinpanemab discontinued after failing to demonstrate clinical benefit and prasinezumab progressing to further evaluation despite not meeting primary endpoints in earlier trials. Active immunisation remains investigational.
Other approaches include gene-regulation strategies, such as antisense oligonucleotides and RNA-based therapies targeting SNCA, as well as methods to enhance lysosomal degradation, autophagy, chaperone-mediated clearance and disrupt α-syn aggregation. However, no disease-modifying therapy has yet been approved.
Cell-replacement therapies aim to restore dopaminergic neurons rather than directly target disease mechanisms. While early foetal tissue transplantation provided proof-of-concept, limitations led to the development of more scalable stem cell-derived dopaminergic progenitor approaches, which are now undergoing clinical evaluation. These therapies may restore function but do not directly address α-syn pathology, neuroinflammation or the broader neurodegenerative environment.
A major challenge across all approaches is timing, as α-syn pathology may begin years before clinical symptoms emerge. Therapies that intervene earlier, before extensive neuronal loss, may therefore offer the greatest potential to alter disease progression.
Natural killer cell-derived extracellular vesicles as a therapeutic platform
These limitations have stimulated interest in therapeutic platforms capable of simultaneously targeting multiple aspects of PD pathogenesis, including α-syn pathology, impaired proteostasis and chronic neuroinflammation. One such emerging approach is the use of NK-EVs. NK cells are best known for their roles in antiviral and antitumour immunity but are increasingly recognised as important regulators of inflammatory responses. In addition to direct cytotoxic activity, NK cells communicate with surrounding cells through cytokine signalling and the release of EVs. These EVs carry proteins, lipids and regulatory RNAs capable of modulating immune responses and cellular homeostasis. As cell-free products, NK-EVs could offer practical advantages over whole-cell therapies, including greater potential for standardisation, storage and large-scale manufacture.
Recent studies have suggested that NK-cell therapies exert neuroprotective effects. In Alzheimer’s disease, repeated administration of high-dose autologous NK cells has been associated with cognitive stabilisation together with reductions in biomarkers of neuroinflammation and proteinopathy, including GFAP, phosphorylated tau and α-syn.[x] These observations suggest that NK-cell-mediated immunomodulation has broader therapeutic applications in neurodegenerative disorders characterised by chronic inflammation and pathological protein aggregation. Consistent with this concept, NK cells regulate inflammatory signalling and have been shown experimentally to interact with extracellular α-syn species, providing a biological rationale for investigating NK cell-derived EVs in PD.[xi]
The therapeutic potential of NK-EVs is therefore of increasing interest. Their cargo includes immune-regulatory proteins, lipids and regulatory RNAs capable of influencing inflammatory responses and cellular homeostasis, while engineered NK-EVs could also serve as vehicles for the targeted delivery of therapeutic molecules.
Within the context of PD, NK-EVs are of particular interest because they may influence several interconnected pathological processes simultaneously, including neuroinflammation, impaired proteostasis and α-syn pathology. However, direct evidence supporting these mechanisms in PD remains limited, and many proposed therapeutic effects are currently based on preclinical observations or extrapolation from other disease models. Together, these properties position NK-EVs as a promising therapeutic platform for PD, with the potential to act across several interconnected pathogenic mechanisms.
Reprogramming neuroinflammation
PD is unlikely to be effectively treated through interventions directed at a single pathogenic mechanism. Therapeutic platforms capable of simultaneously modulating multiple interconnected aspects of disease biology could offer important advantages. NK cell-derived EVs represent one such emerging platform. Their relatively inexpensive production, storability and intrinsic immunomodulatory properties, combined with their ease of transfer across the blood brain barrier and potential to deliver engineered therapeutic cargo, provide a strong biological rationale for further investigation. Through their potential to impact several components of PD pathogenesis and deliver cargo to relevant cells within the brain, NK‑EVs warrant investigation as a biologically grounded, disease‑modifying strategy rather than as symptomatic treatment alone.
Author affiliations
Andrew French1,2,3 PhD, Richard Boyd1,2 PhD, Alice Pébay3 PhD, Alan Trounson 1,2 PhD
1Evinco Therapeutics, 12 Ferntree Place, Notting Hill, Victoria, Australia 3068
2Monash University, Clayton, Victoria, Australia 3068
3The University of Melbourne, Parkville, Victoria, Australia 3010.
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