Background

Mitochondria, the cell’s bioenergetic hubs, comprise four key components: the outer mitochondrial membrane (OMM), the intermembrane space (IMS), the inner mitochondrial membrane (IMM), and the mitochondrial matrix (MM) [1]. They are central to cellular energy metabolism, playing a crucial role in the oxidation of various metabolic substrates, including carbohydrates, fats, and proteins. These substrates are converted into intermediates like acetyl coenzyme A (acetyl-CoA), which then enters the mitochondria for further processing in the tricarboxylic acid (TCA) cycle, underscoring the organelles’ critical role in energy production. Additionally, mitochondria are pivotal in regulating key cellular processes like redox balance, Ca2+ levels, apoptosis initiation, and biomacromolecule balance, thereby influencing cell survival and death [2].

Mitochondrial metabolic pathways predominantly encompass the TCA cycle, oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO) and glutamine (Gln) metabolism. These pathways are integral to the breakdown of biomacromolecules and the generation of energy [3]. Importantly, mitochondria serve as a primary source of reactive oxygen species (ROS), stemming from their involvement in various core metabolic processes. The production of ROS can disrupt the redox network, leading to the oxidation of lipids and proteins, mutations in mitochondrial DNA (mtDNA), and the induction of oxidative stress. These effects are implicated in the initiation and progression of a range of systemic diseases, including cancer, neurodegenerative disorders, diabetes, obesity, ischemic heart disease, hyperthyroidism, and phenylketonuria [4,5,42].

Innovative approaches have been proposed to address these challenges, notably through the integration of mitochondria-targeting molecules within nanoparticle frameworks. For instance, a mitochondria-targeted diketopyrrolopyrrole photosensitizer has been developed, enabling photodynamic and photothermal anti-cancer therapies by targeting mitochondria for heat and singlet oxygen generation [102]. Moreover, gold nanoparticles (AuNPs), enhanced with polymer and folate, accumulate in mitochondria, leading to oxidative stress and apoptosis. Notably, AuNPs disrupt glycolysis, reducing key enzymes through a c-Myc-dependent pathway, causing energy deprivation and inhibiting tumor growth, with minimal impact on non-tumor cells [103].

Inorganic nonmetallic materials

Inorganic nonmetallic nanodrugs have also demonstrated outstanding performance and broad application potential in treating tumors by inducing oxidative stress through targeting mitochondria. For example, iron-oxide magnetic nanoparticles conjugated with Dox effectively target mitochondrial dysfunction in breast cancer cells, inducing oxidative stress that leads to DNA damage, lipid peroxidation, and mitochondrial potential loss. This mitochondrial disruption halts the cell cycle and reduces cell migration, enhancing Dox delivery and increasing cancer cell mortality while potentially lowering toxicity to healthy cells, highlighting their promise in anticancer therapy [104]. Similarly, superparamagnetic iron oxide nanoparticles (SPIONs) demonstrate selective cytotoxicity in vitro against mitochondria isolated from oral cancer. Exposure to SPIONs increases ROS production, disrupts mitochondrial membrane potential, triggers cytochrome c release, and induces mitochondrial swelling. Furthermore, SPIONs decrease succinate dehydrogenase activity in cancerous mitochondria, suggesting their potential as therapeutic agents for oral cancer without significantly affecting non-cancerous cells [105]. Notably, CsI(Na)@MgO nanoparticles, paired with 5-aminolevulinic acid, present a streamlined radiodynamic therapy strategy enhancing tumor suppression. This combination targets mitochondria in cancer cells, increasing ROS production upon X-ray exposure and synergizing with DNA-targeted irradiation to intensify mitochondrial, DNA, and lipid damage [106]. Furthermore, ZnO nanoparticles effectively inhibit proliferation and induce apoptosis in human multiple myeloma cells, primarily through mitochondria-mediated pathways. Exposure to ZnO nanoparticles increases ROS production and decreases ATP levels, enhancing cytochrome C, APAF-1, caspase-9, and caspase-3 expression. This suggests a potent role for ZnO nanoparticles in triggering mitochondrial apoptosis, with minimal cytotoxic effects on peripheral blood mononuclear cells, highlighting their potential as therapeutic agents against multiple myeloma [107].

Organic nanoparticles

Organic nanocarriers offer significant advantages for drug delivery, including enhanced cellular penetration due to their small size and surface modification capabilities. These carriers exhibit high target specificity, improved drug stability, and controlled release mechanisms responsive to specific stimuli like pH or temperature. Additionally, their biocompatibility and low toxicity are crucial for reducing side effects and improving patient tolerance [108]. For instance, red-emissive carbon dots (RCDs) have been developed for PDT, with tunable ROS generation suitable for both aerobic and hypoxic conditions. These RCDs can produce both type I and type II ROS, owing to their specific core sizes and surface states. Their mitochondrial targeting ability enables them to activate cell death via mitochondrial pathways [109]. Interestingly, the nanocarrier HAL/3MA@X-MP, combining hexyl 5-aminolevulinate hydrochloride (HAL) and 3-methyladenine (3MA) within tumor cell-derived microparticles (X-MP), targets tumor cells. HAL induces sonosensitizer accumulation in mitochondria for effective ROS generation and mitochondrial damage, while 3MA inhibits mitophagy and downregulates PD-L1, enhancing immunogenic cell death and impeding immune checkpoint recognition [110]. Moreover, a mitochondria-targeted drug nanocarrier, prepared through host-guest interactions between α-cyclodextrin and polyethylene glycol (PEG), effectively combines a NO donor and a cinnamaldehyde prodrug for cancer treatment. This approach enhances oxidative stress by depleting GSH and generating peroxynitrite in mitochondria, leading to effective apoptosis in cancer cells and showing significant antitumor activity in hepatoma models [111].

Organic/inorganic hybrid nanoparticles

Organic/inorganic hybrid nanomaterials demonstrate significant advantages in drug delivery. By combining the stability and unique optical properties of inorganic components with the biocompatibility of organic components, these materials facilitate efficient drug loading and precise control over drug release, enhancing accumulation at targeted sites [112]. One commonly employed strategy is to integrate metals or metal compounds with other organic components to form composite nanomedicines. For instance, using bio-synthesized gold nanoclusters (Au NCs) paired with mitochondria-targeted aptamer-Pyro conjugates (ApPCs), this approach enhances uptake and mitochondrial targeting within cancer cells. When irradiated, it produces high levels of ROS, effectively killing cancer cells [139]. In addition, some novel bioactive nanosystems have been designed to achieve anti-tumor effects by modulating the mitochondrial metabolic pathways in cancer cells. A mitochondrial-targeting aggregation-induced emission luminogen (AIEgen), DCPy, is combined with living mitochondria to form a bioactive nanohybrid for deep-seated cancer treatment. This nanohybrid generates ROS under microwave irradiation, inducing apoptosis in cancer cells and reprogramming their metabolism from glycolysis to OXPHOS, thereby further enhancing the efficiency of microwave dynamic therapy [140]. Likewise, a novel cancer treatment strategy combines an aggregation-induced emission photosensitizer with bioactive mitochondria (Mito-AIEgen-lipid) to enhance PDT efficiency. This engineered living system shifts cell metabolism towards OXPHOS, inhibiting growth and triggering apoptosis [141].

Fig. 4
figure 4

Nanoparticles targeting mitochondria inhibit OXPHOS to enhance cancer treatment. (A) Organic nanoparticles, such as Bi-Ch, PEG-PCL, and IR-LND@Alb, inhibit OXPHOS and reverse hypoxia, thus enhancing the effectiveness of oxygen-sensitive therapies, including chemotherapy and PDT. (B) Organic/Inorganic hybrid nanoparticles, including PEG-GO@XN, PTX@GO-PEG-OSA, F-AgAps, and Au25(Capt)18, impede mitochondrial respiratory chain enzymes, resulting in increased ROS and reduced ATP production, leading to cell apoptosis and impairing mechanisms of cell migration and invasion while augmenting chemotherapy efficacy. (C) Other novel nanoparticles, such as BLG@TPGS, POPD@ATO@CPT-Py, ZIF-90@ATO@hemin@IRGD, and HM-NPs@G, also inhibit OXPHOS. Contrastingly, Mito-AIEgen-lipid shifts cellular metabolism towards OXPHOS, thereby inhibiting growth, triggering cell apoptosis, and enhancing the efficiency of PDT

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Targeting ATP production

Various nanoparticles have been engineered to target ATP production in cancer cells (Fig. 5). For instance, the TPP-PPG@ICG nanocomposite, integrating a mitochondria-targeting ligand with ICG-loaded graphene, provides synergistic photodynamic and PTT activated by near-infrared light. It disrupts ATP synthesis and mitochondrial function in cancer cells, overcoming drug resistance and leading to cell death. Proven selective and effective in experiments, TPP-PPG@ICG shows promise as a safe and potent treatment for drug-resistant osteosarcoma [142]. In addition, the HNHA-GC nanocomposite disrupts cancer cell metabolism by blocking mitochondrial respiration and glycolysis, crucial for ATP production. It releases calcium, 10-hydroxy CPT, and glucose oxidase (GOD) at tumor sites, causing mitochondrial dysfunction and inhibiting glycolysis. This trigger increased ROS and acidity, enhancing calcium overload [143]. Interestingly, the LMGC nanoparticle is designed with a liquid metal core, surface-functionalized with GOD and coated with calcium carbonate. It achieves therapeutic effects by employing GOD to disrupt glycolysis and increase oxidative stress, while calcium carbonate promotes Ca2+-mediated mitochondrial dysfunction. This dual approach effectively reduces ATP production and lowers heat resistance in tumor cells, thereby improving the effectiveness of PTT against tumors [144]. Notably, an abraxane-like nanoplatform named LCIR effectively depletes ATP by inhibiting mitochondrial complexes and hexokinase II, enhancing NIR-triggered photodynamic and photothermal treatments. This approach significantly reduces tumor size with minimal systemic toxicity, indicating its potential to overcome resistance in conventional cancer therapies [145]. Besides, a novel organic nanocarrier DA-P-SS-T/PTX, modified with acid-cleavable dimethylmaleic anhydride and conjugated with mitochondria-targeting TPP, demonstrates enhanced cellular uptake and specific targeting to mitochondria in tumor environments. It facilitates prolonged blood circulation, effectively targets the mitochondrial outer membrane in tumor cells, leading to decreased membrane potential and ATP levels, thereby inhibiting P-glycoprotein and curtailing both cancer drug resistance and metastasis [193, 194].

Conclusions

In summary, mitochondria are central to cellular energy processes, and their dysfunction is closely associated with cancer development and treatment outcomes. The focus on using multifunctional nanosystems to target mitochondrial metabolism in tumor cells represents a promising approach in cancer therapy. This innovative direction exploits the specific metabolic vulnerabilities of cancer cells, potentially leading to more effective and targeted treatments. Advances in nanomedicine targeting mitochondrial pathways may revolutionize cancer therapy and have implications for managing other diseases characterized by mitochondrial dysregulation.