Table 4 Representative mitochondria-targeting therapeutic regimens

Mitochondrial protein import machinery

Mitochondria-targeting signal peptides

M-ChiP

ROS production

Necrosis, enhanced therapeutic effect with reduced side effect

[580]

AuNR@MSN-ICG-β-CD/Ada-RLA/CS (DMA)-PEG

ROS production; local hyperthermia

Enhanced antitumor effect with minimal side effect

[581]

p53-BakMTS (or BaxMTS) and DBD-BakMTS (or BaxMTS)

Activation of MOMP and caspase-9

Apoptosis

[507]

DOX/CEL-MTS-R8H3

ROS production; inhibition of P-gp efflux activity

Overcoming drug resistance in breast cancer

[509]

Protein nanoparticle

GST-MT-3(Co²⁺) NPs

ROS production; reduction of MMPs

Suppressing tumors and prolonging survival

[508]

Cell-penetrating peptide-based

Cell-penetrating peptide

Pal-pHK-pKV

Targeting the VDAC1-hexokinase-II complex

Amplifying lung cancer cell death

[524]

DGLipo NPs

ROS production

Overcoming multidrug resistance

[582]

TAT-PEG-DOPE system

/

Selectively killing tumor cells

[523]

pHK-PAS

Cytochrome c release; disruption of the mitochondria-HKII association

Apoptosis

[525]

MTP3

Mitochondrion-targeting prodrug (compound 17, doxorubicin-based prodrug)

Mitochondrial depolarization

Enhanced cytotoxicity against human tumor cells while negligible toxicity toward normal cells

[583]

Delocalized lipophilic cation (DLC)-based

Triphenylphosphonium (TPP)

TPP-LND-DOX NPs

Apoptosis

Conquering drug resistance

[243]

TPP-PEG-L

Apoptosis

Enhancing paclitaxel-induced cytotoxicity and antitumor efficacy

[540]

TPGS1000-TPP-Targeting paclitaxel liposomes

Apoptosis

Inhibiting drug-resistant lung cancer

[541]

THMSNs@LMDI

Singlet oxygen generation

Sensitizing A549/MCF-7 cells to doxorubicin

[578]

Fe3O4@Dex/TPP/PpIX/ss-mPEG

Fenton reaction

Improving antitumor therapeutic efficacy

[574]

TPP-PF127-HA

Cytochrome c release; activation of caspase-3 and caspase-9

Eradicating drug-resistant of lung cancer

[497]

Targeted Sunitinib Liposomes and Targeted Vinorelbine Liposomes

Activation of caspase-9 and caspase-3

Treating invasive breast cancer

[584]

Dequalinium (DQA)

DQA-PEG2000-DSPE

Apoptosis

Enhancing the anticancer efficacy against cisplatin-resistant A549 cells

[545]

DQA and folate-loaded functional DOX nanoparticles

Activation of caspase-9 and caspase-3 cascade

Overcoming multidrug-resistant cancers

[546]

Metal complexes

Ir-photoacid generator (PAG)

¹O₂ generation

Killing cancer cells effectively even under hypoxic conditions

[585]

Guanidinium

BZP, TPY, PPY, THPY

ROS elevation

Against cisplatin-resistant A549 cells

[586]

Synthetic secretion system in E. coli

T3SS

enT3SS

Cytotoxic activity

Eliminating tumors and reducing the mortality of tumor-bearing animals

[553]

Others

Coumarin

Bromocoumarin platinum 1

p53 apoptosis pathway

Overcoming cisplatin resistance

[556]

ZIF-90@DDP

/

Overcoming platinum-resistant ovarian cancer

[557]

Berberine (BBR)

Paclitaxel (PTX)-ss-BBR

ROS production; G2/M arrest

Enhancing the effect of CT in A549 cells

[587]

d-(KLAKLAK)2

d-(KLAKLAK)2

Cytochrome c release

Enhancing the anticancer efficacy

[588]

Ion-pair stabilized lipid matrix

Bio-nFeR

Apoptosis;

Modulation of lipid metabolism

Enhanced bioavailability;

Against multiple cancer stem cells

[589]

Enzymatic self-assembly

Enzymatic cleavage of branched peptides

Flag-(C16)2- CLRP

Inhibition of the mitochondrial protein synthesis; Cytochrome c release

Sensitizing cancer cells to cisplatin

[319, 590]