Mitochondria-targeting Cu2-xSe-TPP with dual enzyme activity alleviates Alzheimer's disease by modulating oxidative stress.

Mitochondrial dysfunction in microglia has been implicated as a key pathogenesis of most neurodegenerative diseases including Alzheimer's disease (AD). Abnormal production of reactive oxygen species (ROS) and neuroinflammation caused by mitochondrial oxidative stress are important factors leading to neuronal death in AD. Herein, a "dual brake" strategy to synergistically halt mitochondrial dysfunction and neuroinflammation targeting mitochondria in microglia is proposed. To achieve this goal, (3-carboxypropyl) triphenyl-phosphonium bromide (TPP)-modified Cu2-xSe nanozymes (Cu2-xSe-TPP NPs) with dual enzyme-like activities was designed. Cu2-xSe-TPP NPs with superoxide dismutase-mimetic (SOD) and catalase-mimetic (CAT) activities can effectively scavenge ROS in the mitochondria of microglia and relieve mitochondrial oxidative stress. In vivo studies demonstrated that Cu2-xSe-TPP NPs can alleviate oxidative stress and promote neuroprotection in the hippocampus of AD model mice. In addition, Cu2-xSe-TPP NPs can regulate the polarization of microglia from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, promote Aß phagocytosis and reshape the AD inflammatory microenvironment, thus effectively attenuating AD neuropathology and rescuing cognitive deficits in AD model mice. Taken together, this strategy preventing mitochondrial damage and remodeling the inflammatory microenvironment will provide a new perspective for AD therapy.

Advancements in nano drug delivery system for liver cancer therapy based on mitochondria-targeting.

Based on poor efficacy and non-specific toxic side effects of conventional drug therapy for liver cancer, nano-based drug delivery system (NDDS) offers the advantage of drug targeting delivery. Subcellular targeting of nanomedicines on this basis enables more precise and effective termination of tumor cells. Mitochondria, as the crucial cell powerhouse, possesses distinctive physical and chemical properties in hepatoma cells different from that in hepatic cells, and controls apoptosis, tumor metastasis, and cellular drug resistance in hepatoma cells through metabolism and dynamics, which serves as a good choice for drug targeting delivery. Thus, mitochondria-targeting NDDS have become a recent research focus, showcasing the design of cationic nanoparticles, metal nanoparticles, mitochondrial peptide modification and so on. Although many studies have shown good results regarding anti-tumor efficacy, it is a long way to go before the successful translation of clinical application. Based on these, we summarized the specificity and importance of mitochondria in hepatoma cells, and reviewed the current mitochondria-targeting NDDS for liver cancer therapy, aiming to provide a better understanding for current development process, strengths and weaknesses of mitochondria-targeting NDDS as well as informing subsequent improvements and developments.

Mitochondria-Targeted Gold Biometallization for Photoacoustically Visualized Photothermal Cancer Therapy.

Subcellular biomineralization systems with cellular intervention functions have shown great potential in cancer theranostic applications. However, the lack of subcellular specificity, high ion concentrations, and long incubation time required for biomineralization still limit its in vivo therapeutic efficacy. Herein, we report a mitochondria-targeted polymer-gold complex (TPPM-Au) to realize mitochondrial biometallization, which involves analogous mechanisms during biomineralization, for cancer treatment in vivo. The TPP-containing TPPM-Au delivered more Au3+ selectively into the mitochondria of cancer cells than normal cells, rapidly mineralizing to gold nanoparticles (GNPs) and consuming a large amount of the antioxidant glutathione (GSH). The formed GNPs can further continue consuming GSH with the atomic economy by forming Au-S with GSH, which further results in the accumulation of reactive oxygen species (ROS), thereby impairing mitochondrial function and inducing cell apoptosis. More importantly, TPPM-Au is capable of having superior tumor-penetrating, excellent photothermal and photoacoustic properties, endowing it with the ability to inhibit tumor growth through spatiotemporally monitorable mitochondria-targeted biometallization and photothermal therapy. The mitochondria-targeted gold biometallization theranostic platform provides insight into the application of subcellularly targeted biometallization or biomineralization in cancer therapy.

Two-pronged strategy: A mitochondria targeting AIE photosensitizer for hydrogen sulfide detection and type I and type II photodynamic therapy.

Multifunctional type-I photosensitizers (PSs) for hydrogen sulfide (H2S) detection and photodynamic therapy (PDT) of hypoxia tumors exhibits attractive curative effect but remains a challenging task. Herein, a mitochondria targeted aggregation-induced emission (AIE) photosensitizer TSPy-SS-P was designed and synthesized, which could be used for H2S detection and simultaneously type I and type II PDT. TSPy-SS-P had excellent selectivity and anti-interference abilities for endogenous and exogenous H2S detection in tumor cells. TSPy-SS-P was able to distinguish tumor cells with high level of H2S from normal cells by fluorescence "turn off" response to H2S. In addition, TSPy-SS-P showed type Ⅰ and type Ⅱ reactive oxygen species (ROS) generation ability to effectively ablate hypoxic tumor cells. TSPy-SS-P showed mitochondria targeting capacity which could produce ROS in situ to disrupt mitochondria and promote cell apoptosis. In vivo PDT experiments showcased that TSPy-SS-P had excellent tumor retention capability, effective tumor ablation ability and good biocompatibility. This work provided a two-pronged strategy to design organelles targeted photosensitizers for H2S detection and effective PDT of tumors.

Poly(A) Tail Length of Messenger RNA Regulates Translational Efficiency of the Mitochondria-Targeting Delivery System.

Mitochondria are essential for cellular functions, such as energy production. Human mitochondrial DNA (mtDNA), encoding 13 distinct genes, two rRNA, and 22 tRNA, is crucial for maintaining vital functions, along with nuclear-encoded mitochondrial proteins. However, mtDNA is prone to somatic mutations due to replication errors and reactive oxygen species exposure. These mutations can accumulate, leading to heteroplasmic conditions associated with severe metabolic diseases. Therefore, developing methodologies to improve mitochondrial health is highly demanded. Introducing nucleic acids directly into mitochondria is a promising strategy to control mitochondrial gene expression. Messenger RNA (mRNA) delivery especially offers several advantages such as faster gene expression and reduced risk of genome integration if accidentally delivered to the cell nucleus. In this study, we investigated the effect of the poly(A) tail length of mRNA on the mitochondrial translation to achieve efficient expression. We used a peptide-based mitochondrial targeting system, mitoNEET-(RH)9, comprising a mitochondria-targeting sequence (MTS) and a cationic sequence, to deliver mRNA with various poly(A) tails into the mitochondria. The poly(A) tail length significantly affected translational efficiency, with a medium length of 60 nucleotides maximizing protein expression in various cell lines due to enhanced interaction with mitochondrial RNA-binding proteins. Our findings highlight the importance of optimizing poly(A) tail length for efficient mitochondrial mRNA translation, providing a potential strategy for improving mitochondrial gene therapy. These results pave the way for further exploration of the mechanisms and clinical applications of mitochondrial mRNA delivery systems.

Strongly ROS-Correlated, Time-Dependent, and Selective Antiproliferative Effects of Synthesized Nano Vesicles on BRAF Mutant Melanoma Cells and Their Hyaluronic Acid-Based Hydrogel Formulation.

Cutaneous metastatic melanoma (CMM) is the most aggressive form of skin cancer with a poor prognosis. Drug-induced secondary tumorigenesis and the emergency of drug resistance worsen an already worrying scenario, thus rendering urgent the development of new treatments not dealing with mutable cellular processes. Triphenyl phosphonium salts (TPPSs), in addiction to acting as cytoplasmic membrane disruptors, are reported to be mitochondria-targeting compounds, exerting anticancer effects mainly by damaging their membranes and causing depolarization, impairing mitochondria functions and their DNA, triggering oxidative stress (OS), and priming primarily apoptotic cell death. TPP-based bola amphiphiles are capable of self-forming nanoparticles (NPs) with enhanced biological properties, as commonly observed for nanomaterials. Already employed in several other biomedical applications, the per se selective potent antibacterial effects of a TPP bola amphiphile have only recently been demonstrated on 50 multidrug resistant (MDR) clinical superbugs, as well as its exceptional and selective anticancer properties on sensitive and MDR neuroblastoma cells. Here, aiming at finding new molecules possibly developable as new treatments for counteracting CMM, the effects of this TPP-based bola amphiphile (BPPB) have been investigated against two BRAF mutants CMM cell lines (MeOV and MeTRAV) with excellent results (even IC50 = 49 nM on MeOV after 72 h treatment). With these findings and considering the low cytotoxicity of BPPB against different mammalian non-tumoral cell lines and red blood cells (RBCs, selectivity indexes up to 299 on MeOV after 72 h treatment), the possible future development of BPPB as topical treatment for CMM lesions was presumed. With this aim, a biodegradable hyaluronic acid (HA)-based hydrogel formulation (HA-BPPB-HG) was prepared without using any potentially toxic crosslinking agents simply by dispersing suitable amounts of the two ingredients in water and sonicating under gentle heating. HA-BPPB-HA was completely characterized, with promising outcomes such as high swelling capability, high porosity, and viscous elastic rheological behavior.

Salvaging myocardial infarction with nanoenzyme-loaded hydrogels: Targeted scavenging of mitochondrial reactive oxygen species.

Myocardial infarction resulting from coronary artery atherosclerosis is the leading cause of heart failure, which represents a significant global health burden. The limitations of conventional pharmacologic thrombolysis and flow reperfusion procedures highlight the urgent need for new therapeutic strategies to effectively treat myocardial infarction. In this study, we present a novel biomimetic approach that integrates polyphenols and metal nanoenzymes, inspired by the structure of pomegranates. We developed tannic acid-coated Mn-Co3O4 (MCT) nanoparticles in combination with an injectable collagen hydrogel for the effective treatment of myocardial infarction. The hydrogel enhanced the infarct microenvironment, while the slow-released MCT targets mitochondria to inhibit the post-infarction surge of reactive oxygen species, providing anti-apoptotic and anti-inflammatory effects. RNA sequencing revealed the potential of hydrogels to serve as an interventional mechanism during the post-infarction inflammatory phase. Notably, we found that the hydrogel, when combined with the nanopomegranate-based therapy, significantly improves adverse ventricular remodeling and restores cardiac function in early infarction management. The MCT hydrogel leverages the unique benefits of both MCT nanopomegranates and collagen, demonstrating a synergistic effect. This approach provides a promising example of the potential cooperation between nanomimetic structures and natural biomaterials in therapeutic applications.

Yellow Emissive Carbon Dots - A Robust Nanoprobe for Highly Sensitive Quantification of Jaundice Biomarker and Mitochondria Targeting in Cancer Cells.

The abnormally high level of bilirubin (BR) in biofluids (human serum and urine) indicates a high probability of jaundice and liver dysfunction. However, quantification of BR as the Jaundice biomarker is difficult due to the interference of various biomolecules in serum and urine. To address this issue, we developed a fluorescence-based detection strategy, for which yellow emissive carbon dots (YCDs) were produced from a one-step solvothermal process using phloroglucinol and thionin acetate as chemical precursors. The as-fabricated YCDs exhibited a strong fluorescence peak at the wavelength of 542 nm upon excitation at 390 nm. We used YCDs for detecting BR through the fluorescence turn-off mechanism, unveiling the excellent sensitivity in the linear range of 0.5-12.5 µM with a limit of detection (LOD) of 9.62 nM, which was far below the clinically relevant range. The analytical nanoprobe also offered excellent detection specificity for quantifying BR in real samples. Moreover, the biocompatible fluorescent nanoprobe was successfully employed to target mitochondria in live cancer cells. A colocalization study confirmed that YCDs possessed the ability to target mitochondria and overlapped completely with MitoTracker Red. The developed nanoprobe of YCDs turned out to be straightforward in their synthesis, noninvasive, and can be utilized for biomedical sensors to diagnose the onset of jaundice as well as for mitochondria targeting.

Near-infrared hemicyanine photosensitizer for targeted mitochondrial viscosity imaging and efficient photodynamic therapy.

As a severe threat to human health, cancer has always been one of the most significant challenges facing the medical field. However, there is currently no effective technology or method to diagnose and treat cancer simultaneously. Therefore, developing a new approach that integrates diagnosis and treatment holds promise as a means of achieving personalized and precise cancer therapy. In this study, we developed a novel dual-functional near-infrared mitochondrial-targeted photosensitizer, Hcy-I, which is capable of simultaneously monitoring cellular viscosity and specifically targeting mitochondria for photodynamic therapy. Compared with traditional hemicyanine dyes, the introduction of iodine atoms in Hcy-I enhanced spin-orbit coupling (SOC) and promoted the intersystem crossing (ISC) rate, thereby increasing the efficiency of singlet oxygen (1O2) generation. In vitro experiments demonstrated that Hcy-I exhibited high sensitivity to viscosity variations and efficiently generated 1O2 under 638 nm laser irradiation, with an 1O2 quantum yield of up to 48.9 %. Cell experiments further revealed that this photosensitizer could effectively target mitochondria for photodynamic therapy, disrupting mitochondrial membrane potential and inducing cell death. When treated with Hcy-I at a concentration of 0.8 µM, the survival rate of HepG-2 cells was only 13 %. These results suggested that Hcy-I had the potential to integrate cancer diagnosis and treatment. The research not only promotes the development of photodynamic thereby technology, but also opens up new avenues for the diagnosis and treatment of cancer.

Development of Dual-Targeted Mixed Micelles Loaded with Celastrol and Evaluation on Triple-Negative Breast Cancer Therapy.

Considering that the precise delivery of Celastrol (Cst) into mitochondria to induce mitochondrial dysfunction may be a potential approach to improve the therapeutic outcomes of Cst on TNBC, a novel tumor mitochondria dual-targeted mixed-micelle nano-system was fabricated via self-synthesized triphenylphosphonium-modified cholesterol (TPP-Chol) and hyaluronic acid (HA)-modified cholesterol (HA-Chol). The Cst-loaded mixed micelles (Cst@HA/TPP-M) exhibited the characteristics of a small particle size, negative surface potential, high drug loading of up to 22.8%, and sustained drug release behavior. Compared to Cst-loaded micelles assembled only by TPP-Chol (Cst@TPP-M), Cst@HA/TPP-M decreased the hemolysis rate and upgraded the in vivo stability and safety. In addition, a series of cell experiments using the triple-negative breast cancer cell line MDA-MB-231 as a cell model proved that Cst@HA/TPP-M effectively increased the cellular uptake of the drug through CD44-receptors-mediated endocytosis, and the uptake amount was three times that of the free Cst group. The confocal results demonstrated successful endo-lysosomal escape and effective mitochondrial transport triggered by the charge converse of Cst@HA/TPP-M after HA degradation in endo-lysosomes. Compared to the free Cst group, Cst@HA/TPP-M significantly elevated the ROS levels, reduced the mitochondrial membrane potential, and promoted tumor cell apoptosis, showing a better induction effect on mitochondrial dysfunction. In vivo imaging and antitumor experiments based on MDA-MB-231-tumor-bearing nude mice showed that Cst@HA/TPP-M facilitated drug enrichment at the tumor site, attenuated drug systemic distribution, and polished up the antitumor efficacy of Cst compared with free Cst. In general, as a target drug delivery system, mixed micelles co-constructed by TPP-Chol and HA-Chol might provide a promising strategy to ameliorate the therapeutic outcomes of Cst on TNBC.

Win-win integration: A mitochondria targeted AIE photosensitizer for hypochlorite detection and type I & type II photodynamic therapy.

BACKGROUND: Photodynamic therapy (PDT) is a pioneering and effective anticancer modality with low adverse effects and high selectivity. Hypochlorous acid or hypochlorite (HClO/ClO-) is a type of inflammatory cytokine. The abnormal increase of ClO- in tumor cells is related to tumor pathogenesis and may be a "friend" for the design and synthesis of responsive phototherapy agents. However, preparing responsive phototherapy agents for all-in-one noninvasive diagnosis and simultaneous in situ therapy in a complex tumor environment is highly desirable but still remains an enormously demanding task. RESULTS: An acceptor-π bridge-donor-π bridge-acceptor (A-π-D-π-A) type photosensitizer TPTPy was designed and synthesized based on the phenothiazine structure which was used as the donor moiety as well as a ClO- responsive group. TPTPy was a multifunctional mitochondria targeted aggregation-induced emission (AIE) photosensitizer which could quickly and sensitively respond to ClO- with fluorescence "turn on" performance (19-fold fluorescence enhancement) and enhanced type I reactive oxygen species (ROS) generation to effectively ablate hypoxic tumor cells. The detection limit of TPTPy to ClO- was calculated to be 185.38 nM. The well-tailored TPTPy anchoring to mitochondria and producing ROS in situ could disrupt mitochondria and promote cell apoptosis. TPTPy was able to image inflammatory cells and tumor cells through ClO- response. In vivo results revealed that TPTPy was successfully utilized for PDT in tumor bearing nude mice and exhibited excellent biological safety for major organs. SIGNIFICANCE AND NOVELTY: A win-win integration strategy was proposed to design a tumor intracellular ClO- responsive photosensitizer TPTPy capable of both type I and type II ROS production to achieve photodynamic therapy of tumor. This work sheds light on the win-win integration design by taking full advantage of the characteristics of tumor microenvironment to build up responsive photosensitizer for in situ PDT of tumor.

A Pyridinium fluorophore for the detection of zinc ions under autophagy conditions.

Molecular probes for sensing and imaging of various analytes and biological specimens are of great importance in clinical diagnostics, therapy, and disease management. Since the cellular concentration of free Zn2+ varies from nanomolar to micromolar range during cellular processes and the high affinity Zn2+ imaging probes tend to saturate at lower concentrations of free Zn2+, fluorescence based probes with moderate binding affinity are desirable in distinguishing the occurrence of higher zinc concentrations in the cells. Herein, we report a new, pentacyclic pyridinium based probe, PYD-PA, having a pendant N,N-di(pyridin-2-ylmethyl)amine (DPA) for Zn2+ detection in the cellular environment. The designed probe is soluble in water and serves as a mitochondria targeting unit, whereas the pendent DPA acts as the coordination site for Zn2+. PYD-PA displayed a threefold enhancement in fluorescence intensity upon Zn2+ binding with a 1:1 binding stoichiometry. Further, the probe showed a selective response to Zn2+ over other biologically relevant metal ions with a moderate binding affinity (Ka = 6.29 × 104 M-1), good photostability, pH insensitivity, and low cytotoxicity. The demonstration of bioimaging in SK-BR-3 breast cancer cell lines confirmed the intracellular Zn ion sensing ability of the probe. The probe was successfully applied for real time monitoring of the fluctuation of intracellular free zinc ions during autophagy conditions, demonstrating its potential for cellular imaging of Zn2+ at higher intracellular concentrations.

Targeted mitochondrial nanomaterials in biomedicine: Advances in therapeutic strategies and imaging modalities.

Mitochondria, pivotal organelles crucial for energy generation, apoptosis regulation, and cellular metabolism, have spurred remarkable advancements in targeted material development. This review surveys recent breakthroughs in targeted mitochondrial nanomaterials, illuminating their potential in drug delivery, disease management, and biomedical imaging. This review approaches from various application perspectives, introducing the specific applications of mitochondria-targeted materials in cancer treatment, probes and imaging, and diseases treated with mitochondria as a therapeutic target. Addressing extant challenges and elucidating potential therapeutic mechanisms, it also outlines future development trajectories and obstacles. By comprehensively exploring the diverse applications of targeted mitochondrial nanomaterials, this review aims to catalyze innovative treatment modalities and diagnostic approaches in medical research. STATEMENT OF SIGNIFICANCE: This review presents the latest advancements in mitochondria-targeted nanomaterials for biomedical applications, covering diverse fields such as cancer therapy, bioprobes, imaging, and the treatment of various systemic diseases. The novelty and significance of this work lie in its systematic analysis of the intricate relationship between mitochondria and different diseases, as well as the ingenious design strategies employed to harness the therapeutic potential of nanomaterials. By providing crucial insights into the development of mitochondria-targeted nanomaterials and their applications, this review offers a valuable resource for researchers working on innovative treatment modalities and diagnostic approaches. The scientific impact and interest to the readership lie in the identification of promising avenues for future research and the potential for clinical translation of these cutting-edge technologies.

Recent advances in mitochondria-targeting theranostic agents.

For its vital role in maintaining cellular activity and survival, mitochondrion is highly involved in various diseases, and several strategies to target mitochondria have been developed for specific imaging and treatment. Among these approaches, theranostic may realize both diagnosis and therapy with one integrated material, benefiting the simplification of treatment process and candidate drug evaluation. A variety of mitochondria-targeting theranostic agents have been designed based on the differential structure and composition of mitochondria, which enable more precise localization within cellular mitochondria at disease sites, facilitating the unveiling of pathological information while concurrently performing therapeutic interventions. Here, progress of mitochondria-targeting theranostic materials reported in recent years along with background information on mitochondria-targeting and therapy have been briefly summarized, determining to deliver updated status and design ideas in this field to readers.

Mitochondrial Targeted Cerium Oxide Nanoclusters for Radiation Protection and Promoting Hematopoiesis.

Purpose: Mitochondrial oxidative stress is an important factor in cell apoptosis. Cerium oxide nanomaterials show great potential for scavenging free radicals and simulating superoxide dismutase (SOD) and catalase (CAT) activities. To solve the problem of poor targeting of cerium oxide nanomaterials, we designed albumin-cerium oxide nanoclusters (TPP-PCNLs) that target the modification of mitochondria with triphenyl phosphate (TPP). TPP-PCNLs are expected to simulate the activity of superoxide dismutase, continuously remove reactive oxygen species, and play a lasting role in radiation protection. Methods: First, cerium dioxide nanoclusters (CNLs), polyethylene glycol cerium dioxide nanoclusters (PCNLs), and TPP-PCNLs were characterized in terms of their morphology and size, ultraviolet spectrum, dispersion stability and cellular uptake, and colocalization Subsequently, the anti-radiation effects of TPP-PCNLs were investigated using in vitro and in vivo experiments including cell viability, apoptosis, comet assays, histopathology, and dose reduction factor (DRF). Results: TPP-PCNLs exhibited good stability and biocompatibility. In vitro experiments indicated that TPP-PCNLs could not only target mitochondria excellently but also regulate reactive oxygen species (ROS)levels in whole cells. More importantly, TPP-PCNLs improved the integrity and functionality of mitochondria in irradiated L-02 cells, thereby indirectly eliminating the continuous damage to nuclear DNA caused by mitochondrial oxidative stress. TPP-PCNLs are mainly targeted to the liver, spleen, and other extramedullary hematopoietic organs with a radiation dose reduction factor of 1.30. In vivo experiments showed that TPP-PCNLs effectively improved the survival rate, weight change, hematopoietic function of irradiated animals. Western blot experiments have confirmed that TPP-PCNLs play a role in radiation protection by regulating the mitochondrial apoptotic pathway. Conclusion: TPP-PCNLs play a radiologically protective role by targeting extramedullary hematopoietic organ-liver cells and mitochondria to continuously clear ROS.

Mitochondrial Protein Density, Biomass, and Bioenergetics as Predictors for the Efficacy of Glioma Treatments.

The metabolism of glioma cells exhibits significant heterogeneity and is partially responsible for treatment outcomes. Given this variability, we hypothesized that the effectiveness of treatments targeting various metabolic pathways depends on the bioenergetic profiles and mitochondrial status of glioma cells. To this end, we analyzed mitochondrial biomass, mitochondrial protein density, oxidative phosphorylation (OXPHOS), and glycolysis in a panel of eight glioma cell lines. Our findings revealed considerable variability: mitochondrial biomass varied by up to 3.2-fold, the density of mitochondrial proteins by up to 2.1-fold, and OXPHOS levels by up to 7.3-fold across the cell lines. Subsequently, we stratified glioma cell lines based on their mitochondrial status, OXPHOS, and bioenergetic fitness. Following this stratification, we utilized 16 compounds targeting key bioenergetic, mitochondrial, and related pathways to analyze the associations between induced changes in cell numbers, proliferation, and apoptosis with respect to their steady-state mitochondrial and bioenergetic metrics. Remarkably, a significant fraction of the treatments showed strong correlations with mitochondrial biomass and the density of mitochondrial proteins, suggesting that mitochondrial status may reflect glioma cell sensitivity to specific treatments. Overall, our results indicate that mitochondrial status and bioenergetics are linked to the efficacy of treatments targeting metabolic pathways in glioma.

Research progresses on mitochondrial-targeted biomaterials for bone defect repair.

In recent years, the regulation of the cell microenvironment has opened up new avenues for bone defect repair. Researchers have developed novel biomaterials to influence the behavior of osteoblasts and immune cells by regulating the microenvironment, aiming to achieve efficient bone repair. Mitochondria, as crucial organelles involved in energy conversion, biosynthesis and signal transduction, play a vital role in maintaining bone integrity. Dysfunction of mitochondria can have detrimental effects on the transformation of the immune microenvironment and the differentiation of stem cells, thereby hindering bone tissue regeneration. Consequently, targeted therapy strategies focusing on mitochondria have emerged. This approach offers a wide range of applications and reliable therapeutic effects, thereby providing a new treatment option for complex and refractory bone defect diseases. In recent studies, more biomaterials have been used to restore mitochondrial function and promote positive cell differentiation. The main directions are mitochondrial energy metabolism, mitochondrial biogenesis and mitochondrial quality control. In this review, we investigated the biomaterials used for mitochondria-targeted treatment of bone defect repair in recent years from the perspective of progress and strategies. We also summarized the micro-molecular mechanisms affected by them. Through discussions on energy metabolism, oxidative stress regulation and autophagy regulation, we emphasized the opportunities and challenges faced by mitochondria-targeted biomaterials, providing vital clues for developing a new generation of bone repair materials.

Mitochondria-Targeted Multifunctional Nanoparticles Combine Cuproptosis and Programmed Cell Death-1 Downregulation for Cancer Immunotherapy.

The combination of cuproptosis and immune checkpoint inhibition has shown promise in treating malignant tumors. However, it remains a challenge to deliver copper ions and immune checkpoint inhibitors efficiently and simultaneously to tumors. Herein, a mitochondria-targeted nanoscale coordination polymer particle, Cu/TI, comprising Cu(II), and a triphenylphosphonium conjugate of 5-carboxy-8-hydroxyquinoline (TI), for effective cuproptosis induction and programmed cell death-1 (PD-L1) downregulation is reported. Upon systemic administration, Cu/TI efficiently accumulates in tumor tissues to induce immunogenic cancer cell death and reduce PD-L1 expression. Consequently, Cu/TI promotes the intratumoral infiltration and activation of cytotoxic T lymphocytes to greatly inhibit tumor progression of colorectal carcinoma and triple-negative breast cancer in mouse models without causing obvious side effects.

Upgrading Mitochondria-Targeting Peptide-Based Nanocomplexes for Zebrafish In Vivo Compatibility Assays.

The lack of effective delivery systems has slowed the development of mitochondrial gene therapy. Delivery systems based on cell-penetrating peptides (CPPs) like the WRAP (tryptophan and arginine-rich peptide) family conjugated with a mitochondrial targeting sequence (MTS) have emerged as adequate carriers to mediate gene expression into the mitochondria. In this work, we performed the PEGylation of WRAP/pDNA nanocomplexes and compared them with previously analyzed nanocomplexes such as (KH)9/pDNA and CpMTP/pDNA. All nanocomplexes exhibited nearly homogeneous sizes between 100 and 350 nm in different environments. The developed complexes were biocompatible and hemocompatible to both human astrocytes and lung smooth muscle cells, ensuring in vivo safety. The nanocomplexes displayed mitochondria targeting ability, as through transfection they preferentially accumulate into the mitochondria of astrocytes and muscle cells to the detriment of cytosol and lysosomes. Moreover, the transfection of these cells with MTS-CPP/pDNA complexes produced significant levels of mitochondrial protein ND1, highlighting their efficient role as gene delivery carriers toward mitochondria. The positive obtained data pave the way for in vivo research. Using confocal microscopy, the cellular internalization capacity of these nanocomplexes in the zebrafish embryo model was assessed. The peptide-based nanocomplexes were easily internalized into zebrafish embryos, do not cause harmful or toxic effects, and do not affect zebrafish's normal development and growth. These promising results indicate that MTS-CPP complexes are stable nanosystems capable of internalizing in vivo models and do not present associated toxicity. This work, even at an early stage, offers good prospects for continued in vivo zebrafish research to evaluate the performance of nanocomplexes for mitochondrial gene therapy.

Modular synthesis of pentacyclic-fused pyranoquinoliziniums as organelle-selective fluorescent probes.

On basis of their unique chemical and photophysical properties, and excellent biological activities, quinoliziniums have been widely used in various research fields. Herein, modular synthetic strategies for efficient synthesis of novel fluorescent quinoliziniums by using one-pot and stepwise rhodium(III)-catalyzed C-H annulations were developed. In the one-pot synthesis, the reaction between 2-aryl-4-quinolones (1) and 1,2-diarylalkynes (2) proceeded in a chemo- and regioselective manner to give quinolinone-fused isoquinolines (3) and pentacyclic-fused pyranoquinoliziniums (4). The structural diversity of pentacyclic-fused pyranoquinoliziniums (4) was expanded by the stepwise synthesis from 3 and 2, allowing the strategic incorporation of electron-donating (OMe and OH) and electron-withdrawing (Cl) substituents on the top and bottom parts of the pyranoquinoliziniums (4). These newly synthesized pyranoquinoliziniums (4) exhibited tunable absorptions (455-532 nm), emissions (520-610 nm), fluorescence lifetime (0.3-5.6 ns), large Stokes shifts (up to 120 nm), and excellent fluorescence quantum yields (up to 0.73) upon adjusting the different substituents. The the unique arrangement of N and O atoms and extended π-conjugation of 4 could cause the relocation of HOMO comparing with our previous quinoliziniums. Importantly, pyranoquinoliziniums (4a-4g and 4i) targeted the mitochondria, while 4h was localized in lysosome. Due to the remarkable photophysical properties and the potential for organelle targeting of the novel class of quinoliziniums, they could be further applied for biological, chemical and material applications.