Targeting the Meningeal Compartment to Resolve Chemobrain and Neuropathy via Nasal Delivery of Functionalized Mitochondria. Issue 8 (27th January 2022)

• Record Type: Journal Article
• Authors: Alexander, Jenolyn F.; Mahalingam, Rajasekaran; Seua, Alexandre V.; Wu, Suhong; Arroyo, Luis D.; Hörbelt, Tina; Schedlowski, Manfred; Blanco, Elvin; Kavelaars, Annemieke; Heijnen, Cobi J.
• Is Part Of: Advanced healthcare materials. Volume 11:Issue 8(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-01-27
• Subjects: chemotherapy -- cognition -- encapsulation -- intranasal -- meninges -- pain -- stem cells; Biomedical materials -- Periodicals; 610.28
• DOI: 10.1002/adhm.202102153
• Languages: English
• ISSNs: 2192-2640

Abstract

Abstract: Cognitive deficits (chemobrain) and peripheral neuropathy occur in ∼75% of patients treated for cancer with chemotherapy and persist long‐term in >30% of survivors. Without preventive or curative interventions and with increasing survivorship rates, the population debilitated by these neurotoxicities is rising. Platinum‐based chemotherapeutics, including cisplatin, induce neuronal mitochondrial defects leading to chemobrain and neuropathic pain. This study investigates the capacity of nasally administered mesenchymal stem cell‐derived mitochondria coated with dextran‐triphenylphosphonium polymer (coated mitochondria) to reverse these neurotoxicities. Nasally administered coated mitochondria are rapidly detectable in macrophages in the brain meninges but do not reach the brain parenchyma. The coated mitochondria change expression of >2400 genes regulating immune, neuronal, endocrine and vascular pathways in the meninges of mice treated with cisplatin. Nasal administration of coated mitochondria reverses cisplatin‐induced cognitive deficits and resolves neuropathic pain at a >55‐times lower dose compared to uncoated mitochondria. Reversal of these neuropathologies is associated with resolution of cisplatin‐induced deficits in myelination, synaptosomal mitochondrial integrity and neurogenesis. These findings demonstrate that nasally administered coated mitochondria promote resolution of chemobrain and peripheral neuropathy, thereby identifying a novel facile strategy for clinical application of mitochondrial donation and treating central and peripheral nervous system pathologies by targeting the brain meninges. Abstract : Nasal delivery of mesenchymal stem cell derived‐mitochondria coated with dextran‐triphenylphosphonium reverses chemotherapy‐induced cognitive deficits and pain in mice. Coated mitochondria distribute to the meningeal compartment, alter the meningeal transcriptome and elicit therapeutic effects at a >55‐times lower dose than uncoated mitochondria, providing a promising new strategy to resolve central and peripheral nervous system pathologies by targeting the meningeal compartment.