Administration of nanomedical drugs for neurodegenerative diseases

An exciting review has highlighted the importance of mitochondrial function for neuro-inflammatory and neurodegenerative diseases. This research was published in the journal Pharmaceutics, with the aim of discovering the impact of mitochondrial dysfunction on the overall imbalance within cells.

Study: Nanotechnology-based drug delivery strategies to repair mitochondrial function in neuroinflammatory and neurodegenerative diseases. Image Credit: 3d_man /

The researchers discussed different strategies for the selective targeting of mitochondrial ligands and new solutions involving nanomaterials and drug-loaded nanosystems. These approaches can be developed to repair mitochondrial dysfunction against oxidative stress, prevent cell death, and therefore improve motor and cognitive impairment.

How important are mitochondria for neuroinflammatory and neurodegenerative diseases?

Mitochondria have an important function in cells. In eukaryotic cells, these vital organelles control a range of physiological processes associated with energy production and cellular processes, such as cell death and calcium homeostasis. Mitochondria are also involved in the generation and mediation of reactive oxygen species (ROS), an important part of oxidative stress.

Mitochondrial dynamics refers to coordinated cycles of fission and fusion that control the shape, distribution and size of mitochondria.

Damaged mitochondria are eliminated through a process called mitophagy. Mitophagy involves the selective degradation of mitochondria by autophagy when organelles in mitochondria become defective after being damaged or stressed.

These processes are critical for functioning mitochondria, and any abnormality or imbalance that affects these processes can negatively impact their biology as well as the viability of these organelles.

Studies involving cell cultures, animal models and patients incorporating in vitro and in vivo experimentation has shown that abnormalities within mitochondrial structure and function may be linked to neurodegeneration. In turn, this leads to motor and cognitive deficits in neuroinflammatory (NI) and neurodegenerative (ND) diseases.

These diseases can include multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS). One thing in common between them is that the bioenergetic deficit results from mitochondrial dysfunction.

Impaired function in mitochondria can have serious consequences such as increased ROS production and oxidative stress, further damaging mitochondria and worsening neurodegenerative progression.

However, exciting research into mitochondrial dysfunction and recovery has shown that this restoration of mitochondria and its associated functionality may increase clinical symptoms in cell and animal models of NI and ND disease.

These results illustrate how critical mitochondrial homeostasis restoration strategies are to the development of promising therapies for NI and ND diseases. These therapeutic developments should be specific to intracellular central nervous system (CNS) targets in order to attenuate the systemic side effects experienced by patients diagnosed with these diseases.

Structure and processes involved in the dynamics of healthy and dysfunctional mitochondria. Healthy mitochondria exhibit coordinated and dynamic processes of fusion and fission in order to regulate their morphology, size and number. Following mitochondrial biogenesis guided by the PGC-1α protein, the fusion generates an interconnected mitochondrial network, which is orchestrated by the proteins OPA1, Mfn1 and Mfn2. Fission produces small mitochondria without mtDNA replication due to fragmentation and separation of the mitochondrial network, which is a process driven by dynamin-bound protein (DRP1). The fragmented mitochondria are degraded by mitophagy, which is a process involving the PINK1 and PARKIN proteins. Dysfunctional mitochondria showing structural and functional alterations in neurodegeneration are degraded by mitophagy. Mitochondrial dynamics are maintained by constant activity and a precise balance between biogenesis and clearance of fragmented and defective organelles. MtDNA: mitochondrial DNA, ATP: adenosine triphosphate, ETC: electron transport chain, MM: mitochondrial matrix, mPTP: permeability transition pore, OMM: outer mitochondrial membrane, IMM: inner mitochondrial membrane, PGC-1α: activated receptor by peroxisome proliferator-gamma 1-alpha coactivator, Mfn1 and Mfn2: mitofusins ​​1 and 2, OPA1: optical atrophy protein 1, DRP1: dynamin-bound protein, PINK1: kinase 1 induced by PTEN, PARKIN: Parkin RBR E3 ubiquitin-protein ligase. Image credit: González, L., Bevilacqua, L. and Naves, R.

New strategies targeting mitochondria for NI and ND diseases

Therapeutic efficacy may be reduced when aiming at intercellular targets due to pharmaceutical formulations and biological barriers; however, this is a limitation for the administration of drugs targeting the mitochondria.

The barrier to targeting mitochondria specifically consists of uptake into recipient cells, endosomal escape, lysosomal degradation, and cytoplasmic retention.

Yet, with the exciting advances in nanotechnology, these challenges can be overcome with the introduction of nanosupports or nanoformulations, which can have slow and sustained release of potential drugs to reduce dose and frequency of administrations.

This results in an improvement of drugs in the target tissue and mitochondria without impacting healthy tissue, thus reducing side effects.

Another therapeutic strategy for targeting mitochondrial dysfunction is to target and reduce the levels of ROS produced in the mitochondria via molecules with antioxidant activity, which could aid in neurodegeneration.

Specific nanosystems targeted at mitochondria that contain antioxidants may have the potential to target oxidative stress and reduce the progression of NI and ND diseases.

This review discusses these important strategies with mention of cerium oxide (CeO2) nanoparticles capable of trapping superoxide anions, hydrogen peroxide and peroxynitrite, being internalized by neurons and accumulating at the level of the outer mitochondrial membrane.

The CEO2 nanoparticles reduce levels of reactive nitrogen species, Aβ-induced mitochondrial fragmentation, and neuronal cell death in a cell model of Alzheimer’s disease.

The use of nanotechnology for functionalization and future therapies

Advances in nanotechnology have made it possible to modify and functionalize nanoparticles and materials that have a higher level of targeting.

Nanostructures can be coated with targeting ligands that can directly target the surface of mitochondria; their nanometric size ensures that biological barriers are not an obstacle.

The administration of mitochondria-specific drugs can be achieved by triphenylphosphonium (TPP), a lipophilic cation widely studied as a target agent in mitochondria. The use of this component with antioxidants may be important for mitochondrial targeting.

Antioxidants linked to TPP based on natural hydroxycinnamic derivatives have been shown to have preferential mitochondrial localization, enhanced protection against oxidative damage and mitochondrial defects compared to free molecules in both cell and animal models as well as in ex vivo assay with samples from patients with NI and ND disease.

The use of nanotechnology for drug delivery systems targeting mitochondrial organelles may be a promising therapy for NI and ND diseases, which could be inexpensive and highly effective.

With the direct and indirect role that mitochondrial organelles play in these diseases, the goal of recovering and protecting their structure and functionality would be a potentially important avenue for providing advanced treatment that has yet to be cured.

Continue reading: Progression of pulmonary drug delivery with nanoparticles.


González, L., Bevilacqua, L. and Naves, R., (2021) Nanotechnology-based drug delivery strategies to repair mitochondrial function in neuroinflammatory and neurodegenerative diseases. Pharmaceutical, 13 (12), p.2055. Available at:

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