A CNS-targeted atovaquone nanotherapy mitigates complement activation and neuromuscular degeneration in ALS.
- 1College of Pharmacy, Shenzhen Technology University, 518118, P. R. China.
- 2College of Life and Health Sciences, Northeastern University, 110819, P. R. China.
- 3Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, Liaoning, 110016, China.
Abstract
Complement-mediated glial inflammation and synaptic injury are increasingly implicated in amyotrophic lateral sclerosis (ALS), but clinically translatable complement-modulating therapies remain limited. Atovaquone (ATQ) is an approved, poorly water-soluble small molecule with reported immunomodulatory activity. We investigated whether ATQ could modulate C1qb or C5aR1-associated pathology and whether lactoferrin (Lf)-derived nanomicelles could improve delivery to the spinal cord. ALS spinal-cord single-cell transcriptomic and pathway-enrichment analyses were combined with screening of an FDA-approved drug library, molecular docking and surface plasmon resonance (SPR). Lf-ATQ nanomicelles were characterised by dynamic light scattering, transmission electron microscopy and fluorescence distribution studies. Complement/inflammasome responses were examined in microglial and motor-neuron-microglia models. Therapeutic effects were evaluated in mice expressing the human superoxide dismutase 1 G93A variant (SOD1G93A) by motor testing, compound muscle action potential recording, histology, immunostaining, western blotting and proteomics. Complement genes, particularly C1qb and C5aR1, were enriched in microglia, whereas glutamatergic-synapse and axon-guidance programmes were negatively enriched. In cellular models and SOD1G93A spinal cord, Lf-ATQ reduced C1qb, NLRP3 and multiple inflammatory mediators, attenuated glial reactivity and altered autophagy-related proteins. Treatment preserved rotarod performance, grip strength, gait parameters, compound muscle action potential amplitude and gastrocnemius morphology. Proteomic analysis indicated remodelling of complement/coagulation, vesicular-transport and synaptic modules. These findings support Lf-ATQ as a central nervous system (CNS) -oriented, complement-regulating nanotherapy candidate for ALS. Direct functional target-inhibition assays, quantitative ATQ pharmacokinetics, long-term safety assessment and validation in non-SOD1 models remain necessary before translational conclusions can be drawn.
Related
- A Mechanistic Dissection of Multifaceted Complement Attack in Age-Related Macular Degeneration Reveals the Superiority of C3 Inhibition.
- Pharmacological Activation of Autophagy Ameliorates Neuromuscular-Associated Defects and Extends Lifespan in a Caenorhabditis elegans Model of Spinal Muscular Atrophy.
- Wide-angled proteomics in giant cell arteritis reveals complement pathway activation
- Anti-PLA2R autoantibodies induce complement activation via IgG subclass–dependent epitope pairings in membranous nephropathy
- Characteristics of Patients with Guillain-Barré Syndrome and Fisher Syndrome in Complement Activation: A Retrospective Study
BibTeX
@article{ding2026cnstargeted,
title = {{A CNS-targeted atovaquone nanotherapy mitigates complement activation and neuromuscular degeneration in ALS.}},
author = {Ya-Ning Ding and Madina Bahati and Mei-Qi Li and Pei-Pei Guan and Pu Wang},
journal = {Materials today. Bio},
year = {2026},
month = oct,
doi = {10.1016/j.mtbio.2026.103738},
url = {https://europepmc.org/article/MED/42926777},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - A CNS-targeted atovaquone nanotherapy mitigates complement activation and neuromuscular degeneration in ALS.
AU - Ya-Ning Ding
AU - Madina Bahati
AU - Mei-Qi Li
AU - Pei-Pei Guan
AU - Pu Wang
PY - 2026
DA - 2026/10/07
JO - Materials today. Bio
DO - 10.1016/j.mtbio.2026.103738
UR - https://europepmc.org/article/MED/42926777
AB - Complement-mediated glial inflammation and synaptic injury are increasingly implicated in amyotrophic lateral sclerosis (ALS), but clinically translatable complement-modulating therapies remain limited. Atovaquone (ATQ) is an approved, poorly water-soluble small molecule with reported immunomodulatory activity. We investigated whether ATQ could modulate C1qb or C5aR1-associated pathology and whether lactoferrin (Lf)-derived nanomicelles could improve delivery to the spinal cord. ALS spinal-cord single-cell transcriptomic and pathway-enrichment analyses were combined with screening of an FDA-approved drug library, molecular docking and surface plasmon resonance (SPR). Lf-ATQ nanomicelles were characterised by dynamic light scattering, transmission electron microscopy and fluorescence distribution studies. Complement/inflammasome responses were examined in microglial and motor-neuron-microglia models. Therapeutic effects were evaluated in mice expressing the human superoxide dismutase 1 G93A variant (SOD1G93A) by motor testing, compound muscle action potential recording, histology, immunostaining, western blotting and proteomics. Complement genes, particularly C1qb and C5aR1, were enriched in microglia, whereas glutamatergic-synapse and axon-guidance programmes were negatively enriched. In cellular models and SOD1G93A spinal cord, Lf-ATQ reduced C1qb, NLRP3 and multiple inflammatory mediators, attenuated glial reactivity and altered autophagy-related proteins. Treatment preserved rotarod performance, grip strength, gait parameters, compound muscle action potential amplitude and gastrocnemius morphology. Proteomic analysis indicated remodelling of complement/coagulation, vesicular-transport and synaptic modules. These findings support Lf-ATQ as a central nervous system (CNS) -oriented, complement-regulating nanotherapy candidate for ALS. Direct functional target-inhibition assays, quantitative ATQ pharmacokinetics, long-term safety assessment and validation in non-SOD1 models remain necessary before translational conclusions can be drawn.
SN - 2590-0064
ER -