Nanosystems for Mitochondrial Drug Delivery with Metallic Nanoparticles

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Kamla Pathak	--	3996	2023-07-01 15:52:54	\|
2	format change	Peter Tang	Meta information modification	3996	2023-07-03 05:03:05	\|

This entry is adapted from the peer-reviewed paper 10.3390/molecules28124701

The application of metallic nanoparticles as a novel therapeutic tool has significant potential to facilitate the treatment and diagnosis of mitochondria-based disorders. Subcellular mitochondria have been trialed to cure pathologies that depend on their dysfunction. Nanoparticles made from metals and their oxides (including gold, iron, silver, platinum, zinc oxide, and titanium dioxide) have unique modi operandi that can competently rectify mitochondrial disorders.

metallic nanoparticles mitochondrial dysfunction antioxidants reactive oxygen species calcium homeostasis biocompatibility

1. Introduction

Mitochondria, one of the vital cell organelles, is notable as being oval or bean shaped, as well as for containing a dynamic branched system that consistently divides and fuses in accordance with the regulation of fission and fusion theory ^[1]. Mitochondria are the energy generator of eukaryotic cells, in addition to producing the adenosine triphosphate (ATP) that performs diverse functions, including the biosynthesis and degradation of protein molecules, cell division and respiration, as well as controlling membrane potential. They are adorned with countless cristae in the inner membrane of mitochondria, which are specifically involved in the generation of ATP on a massive scale. Besides the generation of ATP, mitochondria also perform numerous other tasks, such as the biogenesis of amino acids, ROS signaling, calcium ion homeostasis, apoptosis, stem cell monitoring, and the control of innate immunity ^[2]. Further, the bidirectional drive between the nucleus and ATP generator is tightly regulated via the fission (inner membrane) and fusion (outer membrane) of mitochondria. Diverse physical platforms (including signaling pathways, protein–protein interaction, and the regulation of both calcium homeostasis and released reactive oxygen species) occur in the powerhouse of the cell. A number of metabolic processes, such as glycolysis, the Krebs cycle, oxidative phosphorylation, and acetyl CoA oxidation, are executed in the mitochondria, both for the purpose of ATP generation, as well as for dumping released electrons from the various pathways.

The mitochondria has an extremely flexible ultrastructure, intended for the regulation of the bioenergetics flux of the cell. The literature maintains that the sequence of mitochondrial genome (MtDNA) can stabilize maternally inherited diseases. Additionally, the proteomics of mitochondria has described approximately 1000 proteins inside the nuclear genome, of which a mere 13 proteins are coded by the mitochondrial DNA. Hence, quality control of mitochondria is critically important to avoid genome defects, as well as to maintain cell metabolic homeostasis ^[3]. The production, regulation, and consumption of organic molecules are highly required for supporting cell growth and proliferation. Mitochondrial oxygen utilization is key process that generates ATP from these organic compounds and other valuable intermediates. Besides ATP generation, reactive oxygen species (ROS) are also produced during the process of oxidative phosphorylation. These ROS mediate the signaling pathways associated with several basal and adaptive responses controlling both cell and organism hemostasis ^[4].

2. Mitochondrial Dysfunction and Diseases

Human cells comprise more than a thousand replicas of mitochondrial DNA (MtDNA). At the time of birth, these are homoplasmy that may be altered due to pathogens or mutation, and can consequently develop wild type MtDNA, or heteroplasm. The threshold of pathogenic MtDNA varies from person to person, and from organ to organ in the same individual. Abnormal mitochondria dynamics (i.e., fission and fusion), reduced oxidative phosphorylation capacity, and a transformed electron transport chain can each elicit ATP scarcity, alter ROS with poor membrane potential, and cause specific stress signaling responses. The resultant poor mitochondrial protein transportation influences enzyme assembly, which initiates several consequences, such as oxidative damage, proteotoxic stress, mutation, and the exhaustion of MtDNA. The altered morphology and functions of mitochondria can interrupt their nutrient requirements, substrate availability, and genetic signals, causing inherited MtDNA mutations which thus weaken its defense system. Figure 1 outlines the prominent features of the outer, inner, associated plasma membrane and cytosolic barriers.

Figure 1. Interconnected distinguishing features and processes occurring in the mitochondria and associated sites.

Clinical studies have revealed that progressive aging is implicated with mitochondrial impairment, and that the release and accumulation of ROS plays a crucial role in pathogenesis of age-related issues, including neurodegenerative disorders and diabetes. The imbalanced level of generation and oxidation of ROS disturbs the respiratory chain function of mitochondria, altering not only outer/inner membrane permeability, but also calcium homeostasis and high heteroplasmic MtDNA in the sufferers ^[5]. Mitochondrial abnormality (either by MtDNA or nDNA) may occur at any age, and can affect single or multiple organs, e.g., the eye and ear. Both Leber hereditary optic neuropathy and nonsyndromic hearing loss (or deafness) have been reported as being due to abnormal mitochondrial functions. The literature reports noticeable clinical features, such as pigmentary retinopathy, cardiomyopathy, diabetes mellitus, and disorders in central nervous system (i.e., ataxia, dementia, seizures, fluctuating encephalopathy, and migraine), as being associated with the abnormal functioning of mitochondria. Figure 2 illustrates primary and secondary mitochondrial disorders and their operational issues.

Figure 2. Mitochondrial disorders (primary and secondary) and their operational issues.

Recently, Friedreich’s ataxia (a neurodegenerative defect) has been identified due to mitochondrial imbalance of ROS and reactive nitrogen species (RNS). One of the mitochondrial proteins, named frataxin, is encoded and arranged by the FXN gene, which is tremendously expressed in tissues with high metabolic rates. Frataxin is vitally involved in accumulation of the iron–sulfur clusters required for energy production. The latest evidence proposes that this protein deactivates the glutathione peroxidase enzyme, elevates thiol levels, and detoxifies the ROS associated with Friedreich’s ataxia. Hence, targeting this protein may be a possible approach for a drug delivery system ^[6]. Genetic disorders such as Wilson’s disease, hereditary spastic paraplegia, and ethylmalonic aciduria are caused by the mutation of ATP7b, SPG7, and ETHE1 genes, respectively ^[7]. Table 1 compiles different diseases caused by damaged mitochondria, as well as the primary methods of their management.

Table 1. Mitochondrial abnormalities and their management in different human diseases.

Disease	Mitochondrial Abnormalities	Management	Ref.
Cardiovascular diseases	Impaired mitochondrial electron transport chain due to elevated LDL, greater ROS production disturbed cardiac tension, altered cytosolic Ca²⁺ flux, ischemia-reperfusion injury, and other diseases (such as diabetes mellitus)	Control fatty acids and cholesterol level. Regulate enzymes i.e., mitochondrial creatin phosphate, creatin kinase, and ATP synthase. Modulate Ca²⁺ concentration in myocardium.	^[8]
Diabetes	MtDNA mutation Delayed Electron transport chain Increased beta oxidation and lipid accumulation Higher ROS overproduction Disturbed insulin signal pathway Increased intracellular glucose content, and constrained metabolism of glucose	Prevention of ROS and lipid peroxidation. Reverse MtDNA change. Enhance glucose metabolism by inhibiting acetyl-CoA in mitochondria.	^[9]
Kidney	Mitochondrial DNA mutation (complex I–V) Hypomagnesemia Hypokalemia Hypoparathyroidasim Uremic toxins Kidney diseases	Manage Erythropoetin signaling for normal mitochondrial biogenesis and metabolism. Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors, Nrf2-activating triterpenoid, sodium–glucose transporter 2 (SGLT2) inhibitors, and control of carnitine level	^[10]
Alzheimer’s disease	Aggregated Aβ peptide bond with a component that controls mitochondrial permeability ‘cyclophilin D’ Resultant reduction in membrane potential due to opening of pores. Free energy and ROS generated by beta amyloid peptide. Leads to MtDNA mutation and neuronal toxicity.	Inhibition ofAβ peptide clusters binding with cyclophilin D. Restoration of MtDNA and enzyme replacement Inhibit cytochrome c and caspase activity Decrease mitochondrial fission	^[11]
Cancer	Enhanced mitochondrial complex I activity. Mutations in oncogenes Expression of oncoproteins (IDH 1 and 2, SDH and FH) Apoptosis induced factors released. Defective oxidative phosphorylation Hypoxic milieu proliferate condition	Isocitrate dehydrogenase (IDH) 1 and 2 inhibitors Oxidative phosphorylation suppression Antioxidants Mitochondrial complex I and V inhibitors Lactate dehydrogenase (LDH) inhibitors	^[12]

3. Therapeutic Approaches

Approaches such as ‘one size fits all’ and ‘precision medicine’ are often employed for the mitigation of primary mitochondrial disorders. The former manages symptomatic interventions (based on diet, exercise, and pharmacological therapeutics) that initiate mitochondrial biogenesis, provoke nitric acid synthetase, amplify ATP synthesis, control mitochondrial autophagy, and stimulate fission/fusion processes. On the other hand, the precision medicine approach focuses on specialized therapies, i.e., nucleotide supplementation, swapping of damaged MtDNA, gene replacement remedies, the elimination of noxious metabolites, and organ transplantation, if required. Table 2 compiles several therapeutic agents for the regulation of the myriad pathways involved in impaired mitochondria.

Table 2. Therapeutic agents explored for the management of impaired mitochondria.

Therapeutics	Approach	Model	Outcome	Ref.
Upsurging ATP levels
Inosine and Febuxostat	To increase ATP level and hypoxanthine in peripheral blood	Patients with homoplasmic and heteroplasmic mutations	After oral administration, brain natriuretic peptide (specific marker for heart failure) was reduced up to 31%. Moreover, 3.1-fold insulinogenic index was improved, suggesting a promising action of the given treatment.	^[13]
Stimulating mitochondrial biogenesis
Bezafibrate and AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleotide	To initiate biogenesis and activate AMP protein kinase/PGC-1α-dependent pathway	Double recombinant mice overexpressing PGC-1α in skeletal muscles	Stimulation of PPAR/AMPK/PGC-1 alpha increased mitochondrial biogenesis, which monitors the homeostatic pathway and motor improvement in Sco2(KO/KI) animal model	^[14]
5-Aminoimidazole-4-carboxamide ribotide (AICAR)	ATP content and mitochondrial growth were aimed without disturbing membrane potential	CI deficient fibroblasts, such as NDUFS2 and C20ORF7	Fluorescence microscopy detailed the activation of AMP protein kinase with AICAR	^[15]
Nicotinamide riboside (NAD+ precursor)	Effect of nicotinamide in pharmacokinetic parameters and NAD+ level in blood for the treatment of genetic or acquired mitochondrial abnormalities	Impaired mitochondrial murine model	Orally administered nicotinamide riboside was well tolerated, and an increased mean steady state concentration (Css, p = 0.03) two times greater than the baseline NAD+ concentration in blood was observed, whereas average circulating level of NAD+ at day 1 was 27 ± 6 µM.	^[16]
Modulation of the Nitric acid or cGMP/PKG pathway
L-arginine (Nitric acid precursor)	To reduce capacity for nitric acid-based vasodilation	MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) patients	Obtained data suggested that prepared L-Arg infusion was most effective when administered within 4 hrs of the onset of brain disorder symptoms in the acute phase of MELAS sufferers	^[17]
Neural progenitor cells (NPC)	To preserve parental mtDNA and show metabolic shift toward oxidative phosphorylation	Homoplasmic mutation in the mitochondrial gene (MT-ATP6)	Human induced pluripotent stem cells originated NPC, providing a potential tool for mtDNA targeted drug screening to avoid nervous system disorder.	^[18]
Antioxidant therapy
N-acetyl cysteine	Supplementation with N-acetyl cysteine to modify the mitochondrial respiratory chain function	MELAS patients containing common mutation, i.e., m.3243A>G, m.8344A>G	Supplementation with N-acetyl cysteine improved 2-thiomodificationof tRNA, thus regulating protein synthesis.	^[19]
Cysteamine bitartrate	Enhancement of glutathione biosynthesis for the reduction of oxidative stress associated with mitochondrial diseases	Zebrafish model and Caenorhabditis elegans model carrying Complex I defect	Cysteamine bitartrate improved mitochondrial membrane potential in nephropathic cystinosis and cured multiple RC complex diseases in FBXL4 human at 10 to 100 μm concentrations.	^[20]
Inclusion of Redox-Active Molecules
Tc99m-HMPAO	To explore Tc99m-HMPAO for determination of glutathione/protein thiol levels in cerebral blood flow	Pediatric mitochondrial diseased patients	The patients showed improvement in Newcastle score (n = 5, p = 0.028), confirming the potential of Tc99m-HMPAO as a bioimaging marker for the oxidative state of brain.	^[21]
EPI-743	Management of cellular oxidative stress in mitochondrial respiratory chain disease	5-month-old girl suffering from Leigh syndrome	EPI-743 (a potent stress protectant) exhibited improvement in mitochondrial associated issues, i.e., improvement in eye, motor, and bowel movements	^[22]
Monitoring of mitochondrial dynamics
Cytotoxic Necrotizing Factor-1	To control mitochondrial impairment and cell damage	Patient sufferer from m.8344A>G gene	CNF-1 triggered energetic content of mitochondria via activation of actin cycloskeleton in Myoclinic epilepsy with ragged red fibers (MERRF) and increased mitochondrial marker tomo20	^[23]
Modulating mitochondrial autophagy
Rapamycin	Inhibition of mTOR in mitochondrial defect in Leigh syndrome	Ndufs4 wild type mouse	Rapamycin slowed down neurological symptoms and minimized neuroinflammation in brain lesions. It also slowed the formation of glycolytic intermediates.	^[24]
NADH dehydrogenase Ndi1	To replace mitochondrial complex 1 for reoxidation of NADH intramitochondrially.	Transgenic strains of Drosophila	Overexpression of NDI1 relieves aging and manages production of ROS. Deposition of these oxidative damaged markers is declined in aged flies.	^[25]

These approaches may represent a common tactic for the management of primary mitochondrial disorders and can improve an individual’s quality of life, but they are unable to eradicate the cause of the mitochondrial disorder completely.

4. Biological Barrier and Toxicity

There are myriad barriers to designing mitochondria-targeted drug delivery, such as biological barriers and drug toxicity. After reaching to the target cell, intracellular diffusion across the outer and inner mitochondrial membrane is another challenge. Further, mitochondrial complex (I–IV) inhibition within ETC from drugs such as haloperidol and thiothixene have shown critical toxicities ^[26]. Resultantly, neurological disorder such as Parkinson’s disease arise. Nanotechnology-based approaches are promising tools for effectively targeting mitochondria, owing to their narrow size and their efficiency in transporting bioactive agents. Both the mitochondrial membranes experience variable permeability, i.e., the outer membrane allows the permeation of a large array of small molecules, whereas the inner membrane is quite selective for transportation. The reason behind selective permeability through the inner mitochondrial membrane is the presence of specialized channel proteins there ^[27]. Further, the transition pore of the outer mitochondrial membrane is wider than the inner mitochondrial membrane, which facilitates the faster traversal of therapeutics. The highly folded inner mitochondrial membrane is hard and possesses narrow transition slits to separate out the mitochondrial matrix within the inter membrane space. This characteristic morphology of mitochondria also poses a barrier for the passage of drug molecules across matrix. The aforesaid issues create hurdles for targeting mitochondria-based disorders. Several aspects, including high negative membrane potential (−160 to −180 mV), unambiguous protein import mechanism, variable lipophilicity, and idiosyncratic phospholipid composition of inner membrane, are a few key factors considered while designing a mitochondrion-targeted drug delivery system ^[28]. Permeation of the outer membrane of mitochondria is concentration dependent, following passive diffusion. A negative surface charge and mitochondrial membrane potentially drive the production of ATP, in addition to exploiting for mitochondrial targeting through cationic ions and drug molecules via electrostatic interaction. Cardiolipin, another exclusive phospholipid-based component, is confined and produced in the inner mitochondria region. It plays a central role in processing several reactions and processes required for mitochondrial dynamics and respiratory chain complexes ^[29]. Moreover, electrochemical composition and membrane potential are remarkably distinct, compared to cytoplasm. A mitochondrion comprises its own genome in form of a circular DNA containing 37 genes and 16,500 base pairs, essential for protein synthesis. The synthesized 13 proteins are basic components of the mitochondrial electron transport chain, as well as performing the process of oxidative phosphorylation ^[30]. Mitohormesis is related to the damaged adaptive response of mitochondria, and was very first discussed by Ristow et al. in 2010. This process controls mitochondrial homoeostasis and assists organismal senescence. The literature supports that increased age favors defects in mitochondria (mitophagy), replacing new mitochondria via the process of fission and biogenesis ^[31]. Therefore, the mitochondria’s basic functions deteriorate with aging, and can bring about several age-related disorders. In this context, drug-induced cell and mitochondrial toxicities are extensively demarcated in the geriatric population into myriad categories of pharmacological agents ^[32]. For example, troglitazone (an antidiabetic drug) exhibited mitochondrial toxicity and was withdrawn from the market after liver dysfunction was reported. The drug potently disrupted mitochondrial-oriented respiration by inhibiting complexes II, III, IV, and V ^[33]. Another, nefazodone (a serotonin antagonist) has been withdrawn from the market in United States in the year 2004 due to profoundly inhibiting mitochondrial respiratory chain in isolated rat liver cells ^[34]. Biguanides (buformin, metformin, and phenformin) trigger lactic acidosis, which is directly associated with mitochondrial damage due to a surge in lactate production and respiratory inhibition ^[35]. An over-the-counter drug, aspirin is the most prescribed medicine in elderly patients for overcoming of pain and has been reported to inhibit respiratory processes, as well as opening MPT pores and disturbing of glutathione status in mitochondria ^[36]. Another cholesterol lowering drug, simvastatin, obstructs the ETC complexes I, IV, and V, augments calcium release, reduces mitochondrial membrane potential, and thus decreases ATP levels ^[37]. Further, both the in vivo administration of impoverished pharmacokinetic properties and the erratic biodistribution of drugs create challenges for the design of delivery systems. In many instances, therapeutic agents lost their potency with the addition of selective coding for the targeting of mitochondria.

5. Nanoengineered Mitochondria Targeted Approaches

Nanotechnology is able to advance the pharmacokinetic and biodistribution profiles of various drug molecules without altering their pristine molecular form. The nanoformulation of drugs can modify the inherent physicochemical attributes of drugs, such as solubility, lipophilicity, half-life, and minimization of immunogenicity. Successful delivery of bioactive substances with the use of nanoparticles can be realized by customizing particle size, lipophilicity, surface charge, and the addition of specific targeting moieties. Being biocompatible and biodegradable, nanoparticles have proven potential for site-specific delivery ^[38], in addition to the intracellular targeting of subcellular compartments. It is evident that the architecture of mitochondria is highly distinct from other subcellular parts in eukaryotic cells. The occurrence of proton pumps in the inner mitochondrial membrane creates positive charges on the inner folded surface, whereas a negative charge is found in the mitochondrial matrix. This charge gradient develops noticeable transmembrane potential across both outer and inner mitochondrial membranes ^[39]. Molecules such as pyruvates and lipophilic cations (i.e., triphenylphosphonium, rhodamine123, and tetrachlorotetraethylimidacarbocyanine) have been reported on for targeting mitochondria. The cationic lipoidal content of these molecules enables their permeation into the mitochondrial matrix, thus effectively targeting the region of interest. Positively charged nanoparticles induce an electrostatic interaction with the anionic phospholipids of mitochondrial membranes, and are then internalized. Inside the membrane, the nanoparticles rupture and release their drug with the mitochondrial matrix ^[40].

Recently, the cationic liposome-like vesicles known as ‘DQAsomes’ have been highly researched as mitochondria-targeted carriers, being explored to deliver cytotoxic therapeutics or DNA into the highly negative environment of cancer cells ^[41], as these cells experience hyperpolarized membrane potential (−220 mV) compared to the mitochondrial membrane potential of normal cells (−140 mV). Bolalipids containing DQAsomes are vesicle-like structures that are tuned for the delivery of DNA, genes, and peptides inside the mitochondrial matrix. The entrapped component is selectively transported via adorned protein pump machinery on the surface of mitochondria. DQAplexes are hybrid assemblies, comprising membrane liposomes with plasmid DNA for delivery of chemotherapeutics (specifically, into the mitochondria). Vaidya et al. conjugated folic acid on the surface of paclitaxel-entrapped DQAsomes to target overexpressive folate receptors on HeLa (tumor) cells. Outcomes obtained from confocal laser scanning microscopy revealed the enhanced antitumor activity of the designed functionalized DQAsomes, compared to bare DQAsomes ^[42]. However, the modi operandi for restricting the precise mitochondrial targeting of this system were unclear. Other nanoengineered dendrimers with high generation number are abundantly promoted to deliver cytotoxic agents to the mitochondria. Cations (such as triphenylphosphonium, polyamidoamine, and rhodamine) containing dendrimers encompass high net-positive charges and had the ability to carry genetic materials and chemotherapeutic agents at the cell organelle ^[43]. Table 3 summarizes the various nanodrug delivery systems utilized for the management of damaged mitochondria-based diseases.

Table 3. Nanoengineered systems for mitigation of impaired mitochondrial diseases.

Nanodrug Delivery System	Purpose	Model	Outcomes	Relevance	Ref.
Topotecan loaded liposome	Mitochondrial targeted system to overcome resistant related metastases	Multi drug Resistant MCF-7/ADR cell xenografts	Mitochondrial targeted liposomes were 64.84 nm with −0.52 ± 0.08 mV membrane potential. Encapsulation efficiency was ≥95%. They were stable in physiological blood system and exhibited minimal leakage. The system led to release cytochrome C, stimulated caspase 9 and 3, and exhibited superior inhibitory action on the resistant B16 melanoma metastatic mice.	Topotecan localized in mitochondria that exhibited potent inhibitory action on the on the resistant B16 metastatic melanoma.	^[44]
Paclitaxel loaded triphenylphosphine nanomicelles	Inhibition of antiapoptotic Bcl-2	Drug-resistant breast cancer-bearing mouse model with lung metastasis (A549/ADRcells)	The nanomicelles were small (142 ± 8.35 nm) with PDI 0.235 and negative zeta potential (−24.65 ). This system significantly hampered A549/ADR cells and deposited over mitochondria surface. Inhibition of Bcl-2 led to release cytochrome C and triggered caspase 3 and 9, mediating mitochondrial outer membrane permeabilization.	Positively charged nanomicelles adhered inside mitochondria and exhibited apparent multidrug resistant tumor targeting efficacy	^[45]
Curcumin loaded polymeric and lipid nanosuspensions	To neutralize generation of reactive oxygen species due to disturbance of signal proteins in mitochondria.	Olfactory ensheathing cells	Uniform and spherical polymeric and lipid nanosuspensions were of mean sizes 338 nm and 127 nm, respectively, with negatively charged zeta potential. The nanosuspensions were quite stable for more than 135 days. Improved cell viability suggested potential incorporation of curcumin in nanosuspension against hypoxic cells of Olfactory ensheathing cells at the concentration of 5 µM.	Potential intranasal polymeric and lipid nanosuspention was advised for neuroprotective action due to antioxidant property of curcumin.	^[46]
Hydroxyl-terminated polyamidoamine (PAMAM)-N-acetyl cysteine dendrimers	Mitochondrial targeted delivery in oxidative stress-induced glial cell	Rabbit traumatic brain injury (TBI) model	Significantly high localization of drug in mitochondria than nonmodified dendrimer due to potential for attenuation of oxidative stress. Systemic administration in TBI model of rabbit exhibited capability to penetrate BBB and target glial cells due to localization in the white matter of the injured hemisphere.	Colocalization of dendrimer in mitochondria of glial cells in traumatic brain injury	^[47]
Osthole nanoemulsion (OST-NE)	Regulation of apoptosis pathway and mitochondrial oxidative stress.	Alzheimer’s disease model mice	Intranasal delivery of osthole nanoemulsion (mean particle size 2.33 nm) enhanced bioavailability, regulated cholinergic system, maintained mitochondrial potential, and inhibited apoptosis and oxidative stress.	OST-NE lessened upstream modulator Bax, that depolarized mitochondrial membrane potentail and exhibited antiapoptotic effect or neuroprotective action in Alzheimer disease	^[48]
Momordica charantia silver nanoparticles	Uphold mitochondria biogenesis and enhanced the expression of PPARϒ, an energy metabolism coordinator	Pancrease of diabetic rats	Silver nanoparticles possessed irregular/uneven surface and diameter. Contained Momordica charantia enhanced glucose sensitivity in the dibetic rat model at a lower dose of 50 mg/kg by slowing down JAK/STAT and AKT/PI3K pathways in mitochondria.	Developed nanoparticles promoted glucose uptake and insulin secretion via improving mitochondrial biogenesis in pancreas of diabetic rats.	^[49]
Dequalinium embedded DQAsomes	Dicationic amphiphilic was investigated for affinity towards binding with mitochondria DNA.	Plasmid DNA firefly luciferase	Developed DQAsomes created a liposome-like aggregate system in aqueous media that were able to bind with DNA and had efficiency to transfect cells compared to Lipofectin™ reagent.	DQAsomes selectively accumulated in mitochondria of cancerous cells, and suggeted potential use as a nonviral transfection vector in gene delivery system.	^[50]

Metal-based nanoparticles of sizes ranging between 5 and 260 nm were suitable for entry into the mitochondrial matrix. Wang et al. synthesized gold nanorods, in addition to discussing the comparative cellular internalization and intracellular trafficking through the mitochondria, lysosomes, cytoplasm, and endosomes of both normal and cancerous cells. A seed-mediated growth method was utilized to design cetyltrimethylammonium–ammonium bromide wrapped gold nanorods. The average particle size and zeta potential of developed nanorods were 18 ± 0.5 nm and +29.3 ± 0.7 mV, respectively. The prolonged retention and cationic surface charge of the nanorods reduced the mitochondrial membrane potential and generated reactive oxygen species in the mitochondria of lung cancerous cells (A549 cells), which caused apoptosis or cell death ^[51]. Figure 3 outlines the principal mechanism of metallic nanoparticles for targeting mitochondria.

Figure 3. Schematic illustration on the mechanisms of metallic nanoparticles for targeting different pathway signals of mitochondria. PI3K: Phosphatidylinositol 3 Kinase; mTOR: Mammalian Target of Rapamycin; AMPK: Adenosine Monophosphate Activated Protein Kinase; Erk: Extracellular Signal-Regulated Kinase; Akt: Protein Kinase B; MAPK: Mitogen Activated Protein Kinase; ULK1: 112-kDa protein; BNIP3/NIX: Bcl-2 interacting protein 3; PINK1/Parkin-PTEN-induced kinase 1/autoinhibited E3-Ub ligase; SQSTM/P62: Sequestosome 1/p62 scaffold protein; NBR1: Ubiquitous Scaffold Protein; LC3-II: Ubiquitin-Binding Domain (Phosphatidylethanolamine conjugate).

However, the toxicity of metallic nanoparticles is reliant on biophysical characteristics, such as size, surface area, charge, and aggregation. These features affect biodistribution and internalization within organ systems, in addition to changing molecular interactions with receptors or macromolecules ^[52]. Published reports have suggested that there is a direct correlation between the particle size of nanoparticles and their efficiency to generate ROS in vital organs. For instance, silver nanoparticles with 10 nm size displayed superior biodistribution and caused more fatal effects in the liver and spleen cells, compared to the size range 40–100 nm ^[53]. As with the nanoparticle size, shape also affect biodistribution and clearance from the body. Long fibrous metallic nanoparticles exhibited more serious effects and were difficult to remove out from organ systems ^[54]. Similarly charged nanoparticles show greater accumulation in the target site compared to the noncharged ones. Peak et al. investigated the effects of particle size and surface charge of zinc oxide nanoparticles on pharmacokinetic parameters, including biodistribution and clearance upon administration of a single oral dose to rats. It was evident that negatively charged zinc oxide nanoparticles were extensively absorbed by the systemic circulation, compared to those that were positively charged. Zinc oxide particles of 20 nm were swiftly eliminated through the biliary and fecal routes ^[55].

References

Mishra, P.; Chan, D.C. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat. Rev. Mol. Cell Biol. 2014, 15, 634–646.
Kühlbrandt, W. Structure and function of mitochondrial membrane protein complexes. BMC Biol. 2015, 13, 89.
Calvo, S.E.; Mootha, V.K. The mitochondrial proteome and human disease. Annu. Rev. Genom. Hum. Genet. 2010, 11, 25–44.
Shadel, G.S.; Horvath, T.L. Mitochondrial ROS signaling in organismal homeostasis. Cell 2015, 163, 560–569.
Elfawy, H.A.; Das, B. Crosstalk between mitochondrial dysfunction, oxidative stress, and age-related neurodegenerative disease: Etiologies and therapeutic strategies. Life Sci. 2019, 218, 165–184.
Calabrese, V.; Lodi, R.; Tonon, C. D’Agata. V.; Sapienza, M.; Scapagnini, G.; Mangiameli, A.; Pennisi, G.; Stella, A.M.; Butterfield, D.A. Oxidative stress, mitochondrial dysfunction and cellular stress response in Friedreich’s ataxia. J. Neurol. Sci. 2005, 233, 145–162.
Hellebrekers, D.M.; Wolfe, R.; Hendrickx, A.T.; de Coo, I.F.; de Die, C.E.; Geraedts, J.P.; Chinnery, P.F.; Smeets, H.J. PGD and heteroplasmic mitochondrial DNA point mutations: A systematic review estimating the chance of healthy offspring. Hum. Reprod. Update 2012, 18, 341–349.
Bisaccia, G.; Ricci, F.; Gallina, S.; Di Baldassarre, A.; Ghinassi, B. Mitochondrial Dysfunction and Heart Disease: Critical Appraisal of an Overlooked Association. Int. J. Mol. Sci. 2021, 22, 614.
Sergi, D.; Naumovski, N.; Heilbronn, L.K.; Abeywardena, M.; O’Callaghan, N.; Lionetti, L.; Luscombe-Marsh, N. Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet. Front. Physiol. 2019, 10, 532.
Takemura, K.; Nishi, H.; Inagi, R. Mitochondrial Dysfunction in Kidney Disease and Uremic Sarcopenia. Front. Physiol. 2020, 11, 565023.
Misrani, A.; Tabassum, S.; Yang, L. Mitochondrial Dysfunction and Oxidative Stress in Alzheimer’s Disease. Front. Aging Neurosci. 2021, 13, 617588.
Liu, Y.; Shi, Y. Mitochondria as a target in cancer treatment. MedComm 2020, 1, 129–139.
Kamatani, N.; Kushiyama, A.; Toyo-Oka, L.; Toyo-Oka, T. Treatment of two mitochondrial disease patients with a combination of febuxostat and inosine that enhances cellular ATP. J. Hum. Genet. 2019, 64, 351–353.
Viscomi, C.; Bottani, E.; Civiletto, G.; Cerutti, R.; Moggio, M.; Fagiolari, G.; Schon, E.A.; Lamperti, C.; Zeviani, M. In vivo correction of COX deficiency by activation of the AMPK/PGC-1α axis. Cell. Metab. 2011, 14, 80–90.
Golubitzky, A.; Dan, P.; Weissman, S.; Link, G.; Wikstrom, J.D.; Saada, A. Screening for active small molecules in mitochondrial complex I deficient patient’s fibroblasts, reveals AICAR as the most beneficial compound. PLoS ONE 2011, 6, e26883.
Airhart, S.E.; Shireman, L.M.; Risler, L.J.; Anderson, G.D.; Nagana Gowda, G.A.; Raftery, D.; Tian, R.; Shen, D.D.; O’Brien, K.D. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE 2017, 12, e0186459.
Sudo, A.; Sano, H.; Kawamura, N. Determination of the critical time point for efficacy of L-arginine infusion therapy in a case of MELAS with frequent stroke-like episodes. No Hattatsu 2014, 46, 39–43.
Lorenz, C.; Lesimple, P.; Bukowiecki, R.; Zink, A.; Inak, G.; Mlody, B.; Singh, M.; Semtner, M.; Mah, N.; Auré, K.; et al. Human iPSC-Derived Neural Progenitors Are an Effective Drug Discovery Model for Neurological mtDNA Disorders. Cell Stem Cell 2017, 20, 659–674.e9.
Bartsakoulia, M.; Mϋller, J.S.; Gomez-Duran, A.; Yu-Wai-Man, P.; Boczonadi, V.; Horvath, R. Cysteine Supplementation May be Beneficial in a Subgroup of Mitochondrial Translation Deficiencies. J. Neuromuscul. Dis. 2016, 3, 363–379.
Guha, S.; Konkwo, C.; Lavorato, M.; Mathew, N.D.; Peng, M.; Ostrovsky, J.; Kwon, Y.J.; Polyak, E.; Lightfoot, R.; Seiler, C.; et al. Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease. Hum. Mol. Genet. 2019, 28, 1837–1852.
Blankenberg, F.G.; Kinsman, S.L.; Cohen, B.H.; Goris, M.L.; Spicer, K.M.; Perlman, S.L.; Krane, E.J.; Kheifets, V.; Thoolen, M.; Miller, G.; et al. Brain uptake of Tc99m-HMPAO correlates with clinical response to the novel redox modulating agent EPI-743 in patients with mitochondrial disease. Mol. Genet. Metab. 2012, 107, 690–699.
Kouga, T.; Takagi, M.; Miyauchi, A.; Shimbo, H.; Iai, M.; Yamashita, S.; Murayama, K.; Klein, M.B.; Miller, G.; Goto, T.; et al. Japanese Leigh syndrome case treated with EPI-743. Brain Dev. 2018, 40, 145–149.
Fabbri, A.; Travaglione, S.; Maroccia, Z.; Guidotti, M.; Pierri, C.L.; Primiano, G.; Servidei, S.; Loizzo, S.; Fiorentini, C. The Bacterial Protein CNF1 as a Potential Therapeutic Strategy against Mitochondrial Diseases: A Pilot Study. Int. J. Mol. Sci. 2018, 19, 1825.
Johnson, S.C.; Yanos, M.E.; Kayser, E.B.; Quintana, A.; Sangesland, M.; Castanza, A.; Uhde, L.; Hui, J.; Wall, V.Z.; Gagnidze, A.; et al. mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome. Science 2013, 342, 1524–1528.
Sanz, A.; Soikkeli, M.; Portero-Otín, M.; Wilson, A.; Kemppainen, E.; McIlroy, G.; Ellilä, S.; Kemppainen, K.K.; Tuomela, T.; Lakanmaa, M.; et al. Expression of the yeast NADH dehydrogenase Ndi1 in Drosophila confers increased lifespan independently of dietary restriction. Proc. Natl. Acad. Sci. USA 2010, 107, 9105–9110.
Burkhardt, C.; Kelly, J.P.; Lim, Y.H.; Filley, C.M.; Parker, W.D., Jr. Neuroleptic medications inhibit complex I of the electron transport chain. Ann. Neurol. 1993, 33, 512–517.
Pathak, R.K.; Kolishetti, N.; Dhar, S. Targeted nanoparticles in mitochondrial medicine. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2015, 7, 315–329.
Yu, H.; Koilkonda, R.D.; Chou, T.-H.; Porciatti, V.; Ozdemir, S.S.; Chiodo, V.; Boye, S.L.; Boye, S.E.; Hauswirth, W.W.; Lewin, A.S. Gene delivery to mitochondria by targeting modified adenoassociated virus suppresses Leber’s hereditary optic neuropathy in a mouse model. Proc. Natl. Acad. Sci. USA 2012, 109, E1238–E1247.
Kagan, V.E.; Borisenko, G.G.; Tyurina, Y.Y.; Tyurin, V.A.; Jiang, J.; Potapovich, A.I.; Kini, V.; Amoscato, A.A.; Fujii, Y. Oxidative lipidomics of apoptosis: Redox catalytic interactions of cytochrome c with cardiolipin and phosphatidylserine. Free. Radic. Biol. Med. 2004, 37, 1963–1985.
Wallace, D.C.; Fan, W. Energetics, epigenetics, mitochondrial genetics. Mitochondrion 2010, 10, 12–31.
Ristow, M.; Zarse, K. How increased oxidative stress promotes longevity and metabolic health: The concept of mitochondrial hormesis (mitohormesis). Exp. Gerontol. 2010, 45, 410–418.
Will, Y.; Shields, J.E.; Wallace, K.B. Drug-Induced Mitochondrial Toxicity in the Geriatric Population: Challenges and Future Directions. Biology 2019, 8, 32.
Nadanaciva, S.; Dykens, J.A.; Bernal, A.; Capaldi, R.A.; Will, Y. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration. Toxicol. Appl. Pharmacol. 2007, 223, 277–287.
Dykens, J.A.; Jamieson, J.D.; Marroquin, L.D.; Nadanaciva, S.; Xu, J.J.; Dunn, M.C.; Smith, A.R.; Will, Y. In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol. Sci. 2008, 103, 335–345.
Dykens, J.A.; Jamieson, J.; Marroquin, L.; Nadanaciva, S.; Billis, P.A.; Will, Y. Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically poised HepG2 cells and human hepatocytes in vitro. Toxicol. Appl. Pharmacol. 2008, 233, 203–210.
Raza, H.; John, A. Implications of altered glutathione metabolism in aspirin-induced oxidative stress and mitochondrial dysfunction in HepG2 cells. PLoS ONE 2012, 7, e36325.
Bonifacio, A.; Mullen, P.J.; Mityko, I.S.; Navegantes, L.C.; Bouitbir, J.; Krähenbühl, S. Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo. Arch. Toxicol. 2016, 90, 203–215.
Marrache, S.; Pathak, R.K.; Darley, K.L.; Choi, J.H.; Zaver, D.; Kolishetti, N.; Dhar, S. Nanocarriers for tracking and treating diseases. Curr. Med. Chem. 2013, 20, 3500–3514.
Farokhzad, O.C.; Langer, R. Impact of nanotechnology on drug delivery. ACS Nano 2009, 3, 16–20.
Marrache, S.; Dhar, S. Engineering of blended nanoparticle platform for delivery of mitochondriaacting therapeutics. Proc. Natl. Acad. Sci. USA 2012, 109, 16288–16293.
Bae, Y.; Jung, M.K.; Lee, S.; Song, S.J.; Mun, J.Y.; Green, E.S.; Han, J.; Ko, K.S.; Choi, J.S. Dequalinium-based functional nanosomes show increased mitochondria targeting and anticancer effect. Eur. J. Pharm. Biopharm. 2018, 124, 104–115.
Vaidya, B.; Paliwal, R.; Rai, S.; Khatri, K.; Goyal, A.K.; Mishra, N.; Vyas, S.P. Cell-selective mitochondrial targeting: A new approach for cancer therapy. Cancer Ther. 2009, 7, 141–148.
Choi, Y.S.; Cho, T.S.; Kim, J.M.; Han, S.W.; Kim, S.K. Amine terminated G-6 PAMAM dendrimer and its interaction with DNA probed by Hoechst 33258. Biophys. Chem. 2006, 121, 142–149.
Yu, Y.; Wang, Z.H.; Zhang, L.; Yao, H.J.; Zhang, Y.; Li, R.J.; Ju, R.J.; Wang, X.X.; Zhou, J.; Li, N.; et al. Mitochondrial targeting topotecan-loaded liposomes for treating drug-resistant breast cancer and inhibiting invasive metastases of melanoma. Biomaterials 2012, 33, 1808–1820.
Wang, H.; Zhang, F.; Wen, H.; Shi, W.; Huang, Q.; Huang, Y.; Xie, J.; Li, P.; Chen, J.; Qin, L.; et al. Tumor- and mitochondria-targeted nanoparticles eradicate drug resistant lung cancer through mitochondrial pathway of apoptosis. J. Nanobiotechnol. 2020, 18, 8.
Bonaccorso, A.; Pellitteri, R.; Ruozi, B.; Puglia, C.; Santonocito, D.; Pignatello, R.; Musumeci, T. Curcumin Loaded Polymeric vs. Lipid Nanoparticles: Antioxidant Effect on Normal and Hypoxic Olfactory Ensheathing Cells. Nanomaterials 2021, 11, 159.
Sharma, A.; Liaw, K.; Sharma, R.; Zhang, Z.; Kannan, S.; Kannan, R.M. Targeting Mitochondrial Dysfunction and Oxidative Stress in Activated Microglia using Dendrimer-Based Therapeutics. Theranostics 2018, 8, 5529–5547.
Song, Y.; Wang, X.; Wang, X.; Wang, J.; Hao, Q.; Hao, J.; Hou, X. Osthole-Loaded Nanoemulsion Enhances Brain Target in the Treatment of Alzheimer’s Disease via Intranasal Administration. Oxidative Med. Cell. Longev. 2021, 2021, 8844455.
Elekofehinti, O.O.; Ayodele, O.C.; Iwaloye, O. Momordica charantia nanoparticles promote mitochondria biogenesis in the pancreas of diabetic-induced rats: Gene expression study. Egypt. J. Med. Hum. Genet. 2021, 22, 80.
Weissig, V.; Lasch, J.; Erdos, G.; Meyer, H.W.; Rowe, T.C.; Hughes, J. DQAsomes: A novel potential drug and gene delivery system made from Dequalinium. Pharm. Res. 1998, 15, 334–337.
Wang, L.; Liu, Y.; Li, W.; Jiang, X.; Ji, Y.; Wu, X.; Xu, L.; Qiu, Y.; Zhao, K.; Wei, T.; et al. Selective targeting of gold nanorods at the mitochondria of cancer cells: Implications for cancer therapy. Nano Lett. 2011, 11, 772–780.
Kreyling, W.G.; Semmler-Behnke, M.; Seitz, J.; Scymczak, W.; Wenk, A.; Mayer, P.; Takenaka, S.; Oberdörster, G. Size dependence of the translocation of inhaled iridium and carbon nanoparticle aggregates from the lung of rats to the blood and secondary target organs. Inhal. Toxicol. 2009, 21, 55–60.
Recordati, C.; De Maglie, M.; Bianchessi, S.; Argentiere, S.; Cella, C.; Mattiello, S.; Cubadda, F.; Aureli, F.; D’Amato, M.; Raggi, A.; et al. Tissue distribution and acute toxicity of silver after single intravenous administration in mice: Nano-specific and size-dependent effects. Part. Fibre Toxicol. 2016, 13, 12.
Zoroddu, M.A.; Medici, S.; Ledda, A.; Nurchi, V.M.; Lachowicz, J.I.; Peana, M. Toxicity of nanoparticles. Curr. Med. Chem. 2014, 21, 3837–3853.
Paek, H.J.; Lee, Y.J.; Chung, H.E.; Yoo, N.H.; Lee, J.A.; Kim, M.K.; Lee, J.K.; Jeong, J.; Choi, S.J. Modulation of the pharmacokinetics of zinc oxide nanoparticles and their fates in vivo. Nanoscale 2013, 5, 11416–11427.

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