Manipulating biological processes and organelles within cells has emerged as a key strategy to influence cellular physiological functions. Mitochondria are the power source of cells and play a vital role in the development and progression of tumors.
On September 17, 2024, Wang Ruibing and Gao Lei of the University of Macau jointly communicated inAdvanced MaterialsOnline is titled“Tyrosinase-Woven Melanin Nets for Melanoma Therapy via Targeted Mitochondrial Tethering and Enhanced Photothermal Treatment”of research papers.Inspired by tyrosinase catalyzing melanin formation in melanoma cells, the study developed a method of targeting mitochondrial cross-linking in melanoma cells with a polysaccharide dual-functionalized with tyrosine and triphenylphosphine (TPP).
It intricately weaves the melanin network within the cell, acts as a tether for the mitochondria, and effectively slows down tumor metabolism through the transformation of the nanoparticle network. Tyrosinase acts as a "needle," while the functionalized polysaccharide acts as a "rope," successfully building a network inside the cell. In addition, tyrosinase-catalyzed tyrosine crosslinking not only promotes the production of artificial melanin, but also improves the photothermal conversion efficiency of melanoma cells, thereby inhibiting tumor growth.The study reveals a non-drug approach to modulate the physiological activity of organelles, allowing for photothermal therapy of cancer while manipulating cellular functions.
In recent years, traditional anti-tumor drugs combined with targeted therapy, immunotherapy, phototherapy and radiotherapy can rapidly relieve the symptoms of patients by inhibiting the growth of tumor cells, thereby greatly improving the overall tumor treatment effect and increasing the survival rate of patients. However, the effect of traditional anti-tumor chemotherapy drugs is often hindered by complex targets and pathways, lack of selectivity, serious side effects and limited efficacy. Even if combined with other treatment methods, it can not completely eradicate the tumor and retain normal tissues.
In view of the fact that the occurrence, development and metastasis of tumor are closely related to intracellular organelles and macromolecules, regulating the synthesis of intracellular organelles and macromolecules has become a non-drug anti-tumor strategy, which is characterized by controllable, safe and efficient. Different from traditional chemotherapy, this method is expected to achieve targeted and effective anti-tumor without drug resistance.
As the "power factory" of cells, mitochondria are one of the most important organelles and play a key role in the coordination of cell survival and apoptosis.
. On the one hand, mitochondria can produce energy, maintain normal proliferation and differentiation of cells, and control cell growth and cell cycle. On the other hand, mitochondria play an important role in a variety of metabolic activities, including cell information transmission and apoptosis.Therefore, many mitochondrial-targeted therapeutics can induce mitochondrial dysfunction to treat tumors, including reducing ATP, reducing mitochondrial membrane potential, regulating oxidative phosphorylation, and disrupting redox homeostasis. However, some methods can only regulate a single signal pathway, and lack of targeting to cancer cells, resulting in insufficient therapeutic effect.
Since the functions of ATP production, aerobic respiration, oxidative phosphorylation, and redox homeostasis are involved in all aspects of tumorigenesis and development, disrupting whole mitochondria and regulating their overall morphology and function may be a potential strategy for tumor suppression.
The advent of synthetic biology has facilitated the application of endogenous enzymes for precise catalysis and the production of functional macromolecules within specific cells.
The process of melanin synthesis in melanocytes involves the overexpression of tyrosinase catalyzing the oxidation of tyrosine. This enzymatic process has been used to produce dopaquinone (a melanin precursor), dopa or dopa pigment, and finally various biological molecules such as melanin.In the melanogenesis pathway, L-tyrosine is first hydroxylated to L-dihydroxyphenylalanine (L-DOPA), which is further oxidized by tyrosinase to dopaquinone, a common intermediate in the eumelanin and pheomelanin pathways. The reaction rate and type of intermediates are affected by tyrosinase-related protein 1(TRP1/TYRP1), tyrosinase-related protein 2(TRP2/TYRP2/DCT) and physical and physical and chemical environment (metal ions such as Mn
2 or Cu
2 , alkaline pH and thiol concentration).
At the same time, melanin itself and its reactive intermediates exhibit high cytotoxic, genotoxic and mutagenic activity, induce the development of melanoma and resistance to immunotherapy by stimulating glycolysis and activating hypoxia-inducible factor 1-α, immunosuppressive effects, and play a key role in regulating cell metabolism. Among them, the dopa produced by melanoma may pass through the blood-brain barrier and be converted into catecholamines, which affect the central nervous system and release neuroendocrine mediators to cause metabolic changes.
Conversely, inhibition of melanin production by blocking the catalytic site of tyrosinase enhanced the immunotoxic activity of melanoma cells. Therefore, the authors hypothesized that tyrosinase could act as an endogenous enzyme to induce intracellular polymerization of targeted mitochondrial material and drive its in situ assembly near the mitochondria of melanocytes.
In this study, a hyaluronic acid dual-functionalized with tyrosine and triphenylphosphonium (TPP), HA-Tyr-TPP, was synthesized to achieve targeted biosynthesis through tyrosinase-catalyzed cross-linking at melanocyte mitochondria, aiming to induce melanoma mitochondrial damage while promoting in situ biosynthesis of photothermal agents in melanocytes.First, the amphiphilic HA-Tyr-TPP self-assemble into nanoparticles. Subsequently, due to intracellular dilution below the critical micelle concentration (CMC) and the presence of hyaluronidase, the nanoparticles are dispersed into polymer chains that selectively target the mitochondrial surface through TPP-mitochondrial interactions. Finally, enzyme-catalyzed covalent cross-linking and non-toxic linear hyaluronic acid as the raw material skeleton material, weaving a network of bound mitochondria within the cell.
Due to the presence of the mitochondrial targeting group (TPP) in the structure of the HA-Tyr-TPP, the HA-Tyr-TPP can effectively target the mitochondrial surface after entering the cell.There is a large amount of tyrosine in the structure of HA-Tyr-TPP, which will undergo oxidative dimerization under the catalysis of tyrosinase, resulting in multiple HA-Tyr-TPP cross-linking, which effectively induces mitochondrial aggregation, thus affecting its physiological function. Mitochondrial aggregation was demonstrated in vitro and in vivo, with a significant inhibitory effect on tumor growth.Remarkably, the authors found that induction of an artificial melanin network within melanoma cells increased the photothermal conversion efficiency, thereby enhancing the therapeutic effect of HA-Tyr-TPP. This method regulates the morphology, structure and function of organelles through biosynthesis, which lays the foundation for precision cancer treatment.
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