Table 3.
Comparative overview of mitochondrial targeting strategies for neurodegenerative diseases.
| Strategy category | Representative agents/platforms | BBB penetration | Mitochondrial selectivity | Dose-limiting toxicity | Clinical stage | Reproducibility/scalability | Primary translational bottlenecks |
|---|---|---|---|---|---|---|---|
| Lipophilic Cations (TPP+ conjugates) | MitoQ (Murphy and Smith, 2007; Smith et al., 2003), SkQ1 (Skulachev et al., 2009), MitoTEMPO (Dikalov and Harrison, 2014; Trnka et al., 2008), MitoVitE (McCormick et al., 2016; Plecitá-Hlavatá et al., 2009) | Moderate | High | High at elevated conc. (membrane disruption) | Phase II (MitoQ in PD/AD) | Good | ΔΨm dependence; chronic safety; restricted cargo range |
| Szeto–Schiller Peptides (SS peptides) | SS-31/Elamipretide (Tung et al., 2025; Mitchell et al., 2020; Du et al., 2024), SS-20 (Chavez et al., 2020) | Low–Moderate | High | Low; generally well-tolerated | Phase II (cardiac/renal; limited NDD data) | Moderate | BBB penetration; proteolytic degradation; NDD trial data limited |
| Mitochondria-Penetrating Peptides (MPPs) | XJB peptides (Xun et al., 2012; Hara et al., 2024), P110 (Rios et al., 2023), custom MPP constructs (Abe et al., 2023; Schmitt and Wennemers, 2025) | Low–Moderate | Moderate–High | Moderate; sequence-dependent | Preclinical | Moderate | Stability; synthesis cost; in vivo BBB data lacking |
| Synthetic Nanocarriers (liposomes, polymeric NPs, dendrimers) | TPP+-liposomes (Sun et al., 2023; Zielonka et al., 2017), PLGA-b-PEG-TPP (Kuperkar et al., 2024), PAMAM dendrimers (Li et al., 2018), MITO-Porter (Kumar et al., 2024) | Moderate–High | Moderate | Variable; cationic motifs may perturb membranes | Preclinical (select Phase I) | Low–Moderate | Batch reproducibility; endosomal escape; in vivo clearance; scale-up |
| Biomimetic & Cell-Derived Systems (membrane-coated NPs, EVs) | Macrophage/RBC membrane-coated NPs (Han et al., 2021; Chen W. et al., 2023), exosomes (Eo et al., 2024; Jia et al., 2018), mitochondria-derived vesicles (Hayakawa et al., 2016; Kim J. et al., 2023) | High | Moderate | Low (favorable immunocompatibility) | Preclinical | Low | Standardization; manufacturing scalability; immune variability across donors |
| Stimuli-Responsive Platforms (pH/ROS/photo-triggered) | ROS-cleavable nanocarriers (Saravanakumar et al., 2017; Zhang et al., 2019), pH-sensitive polymers (Meng J.-L. et al., 2025; Han et al., 2021), photoresponsive systems (Xiao et al., 2025; Lee S.-Y. et al., 2023) | Moderate | Moderate–High | Moderate; activation specificity critical | Preclinical | Low–Moderate | CNS pharmacokinetics; stimulus sensitivity vs. stability trade-off; phototoxicity risk |
| Coordination Compounds & Receptor-Guided Ligands | EUK-134/Mn-salen (Chen J. et al., 2025; Jomova et al., 2023), Ru/Ir complexes (Krasnovskaya et al., 2020; Prathima et al., 2023), RVG29 (Han et al., 2021), CT51 (Cilibrizzi et al., 2023) | Low–Moderate | Moderate | Variable; metal toxicity a concern | Preclinical | Moderate | Targeting specificity; metal clearance safety; limited in vivo NDD validation |
| Mitochondrial Transplantation (Mitotherapy) | Isolated mitochondria via intracerebral/intranasal/IV (Kubat et al., 2025; Liu et al., 2021; Hayakawa et al., 2016), exosome-assisted delivery (Eo et al., 2024; de Assis Fernandes Caldeira et al., 2025) | Variable | High | Immunogenicity risk; donor variability | Preclinical (early clinical in cardiac) | Low | Scalability; stability of isolated mitochondria; immune compatibility; delivery route optimization |
| Mitochondrial genome editing | mitoZFN (Shoop et al., 2023), mitoTALEN (Gammage et al., 2018; Silva-Pinheiro et al., 2023), DdCBE/CRISPR-independent base editor (Mok et al., 2020; Lee S.-Y. et al., 2023; Raguram et al., 2022) | Low | High | Off-target editing; delivery vector toxicity | Preclinical | Low | Delivery of large editing complexes into mitochondria; off-target risk; long-term safety; limited NDD models |