Mitochondrial Targeting Strategies in Drug Delivery Systems

Targeting therapeutics to mitochondria offers a route to enhance efficacy and overcome resistance in a range of diseases by exploiting the organelle’s unique membrane potential and metabolic functions. Strategies centre on three main approaches: the use of lipophilic cations, stimuli-responsive carriers and peptide or ligand-based targeting. Lipophilic cations such as triphenylphosphonium accumulate selectively within the negatively charged mitochondrial matrix. Stimuli-responsive systems harness tumour acidity, pH gradients or redox conditions to trigger drug release and surface charge reversal, thereby improving cellular uptake and mitochondrial localisation. Peptide- and ligand-based tactics employ mitochondrial targeting sequences or small-molecule moieties to direct nanocarriers across subcellular barriers. Nanoparticle platforms—including liposomes, polymeric micelles and inorganic or biomimetic constructs—allow fine control of size, surface charge and release kinetics. Collectively, these approaches address challenges in chemoresistance, neurodegeneration and metabolic disorders by promoting precise subcellular delivery, minimising off-target effects and enabling synergistic combinations of therapeutic agents.

Research from Nature Portfolio

Foundational work demonstrated a pH-sensitive micellar system that co-delivers doxorubicin conjugated to dequalinium and free doxorubicin to both mitochondria and nucleus. Under acidic conditions, the carrier exposes positively charged moieties that facilitate mitochondrial membrane permeation, inducing outer membrane depolarisation and apoptosis in drug-resistant tumour models. In vivo studies in resistant xenograft mice revealed enhanced tumour suppression without systemic toxicity, underscoring the potential of dual subcellular compartment delivery to overcome chemoresistance.

Mitochondrial Targeting Strategies in Drug Delivery Systems publication trend

The graph below shows the total number of articles in mitochondrial targeting strategies in drug delivery systems across all publications each year (not limited to Nature Index journals).

Technical terms

Triphenylphosphonium (TPP): A lipophilic cation that accumulates within mitochondria by exploiting the negative membrane potential.

pH-sensitive nanocarrier: A delivery system designed to alter charge or structure in response to acidic environments, enhancing cellular uptake and endosomal escape.

Redox-responsive delivery: A strategy employing disulfide or other cleavable linkers that degrade in reducing intracellular compartments, releasing their payload.

Macropinocytosis: A cellular uptake mechanism involving non-selective engulfment of extracellular fluid, often exploited by larger nanoparticles.

References

1. Tumor- and mitochondria-targeted nanoparticles eradicate drug resistant lung cancer through mitochondrial pathway of apoptosis. Journal of Nanobiotechnology (2020).
2. Mitochondria‐targeted nanoparticles in treatment of neurodegenerative diseases. Exploration (2021).
3. Dual subcellular compartment delivery of doxorubicin to overcome drug resistant and enhance antitumor activity. Scientific Reports (2015).
4. pH-activated, mitochondria-targeted, and redox-responsive delivery of paclitaxel nanomicelles to overcome drug resistance and suppress metastasis in lung cancer. Journal of Nanobiotechnology (2021).