Introduction

Globally, cancer incidences and mortality rates are rapidly increasing [1]. Traditional treatment options, such as surgery, chemotherapy, and radiotherapy are limited by low efficacies, drug resistance and significant side effects [2, 3]. Chronic skin wound healing and bone defect repair are common clinical challenges [4, 5]. Rapid advances in nanomedicine have facilitated extensive research in multifunctional light-induced nanoplatforms for cancer and tissue regeneration [6, 7]. Photothermal agents (PTAs) irradiated by specific light wavelengths can induce local hyperthermia by absorbing photon energy and converting the increased kinetic energy into thermal energy. This process, known as photothermal therapy (PTT), is a highly effective and non-invasive treatment method that can induce cancer cell or pathogenic bacterial death [8,9,10]. Moreover, PTT can facilitate other therapies by improving tissue perfusion and enhancing cell membrane permeability. These effects can enhance the overall therapeutic effects and overcome the limitations associated with single treatment approaches [11, 12]. Various synergistic therapies have been developed by combining PTT with other modalities, such as chemotherapy, chemodynamic therapy (CDT), and photodynamic therapy (PDT) [13,14,15,16].

Compared with other noble metal nanoparticles, copper nanoparticles have gained significant attention due to their high natural content and cost-effectiveness [17]. As an indispensable trace element in the human body, copper is directly involved in a variety of biological processes and not only promotes angiogenesis and wound healing, but also has significant antibacterial advantages [18]. Copper incorporated nanomaterials (CINMs) have an intense and tunable localized surface plasmon resonance (LSPR) in the near-infrared (NIR) biological window, which brings excellent photothermal conversion efficiency (PCE) for PTT and photoacoustic imaging (PAI) [19,20,21,22]. CINMs have good catalytic properties and mediate Fenton-like reactions more efficiently than iron-based nanomaterials under a wide range of pH conditions [23]. CINMs can also function as photosensitizers to induce bacterial and tumor cell death via PDT [24, 25]. The optical properties and catalytic activities of CINMs can be improved by adjusting their shapes, sizes and composition [17]. Given these properties, the significance of CINMs has been investigated in various biomedical applications, such as tumor imaging and treatment, and tissue regeneration [26,27,28,29,30,31]. As an excellent candidate for personalized nanomedicines, CINMs can provide a platform for combination of multiple therapeutic and diagnostic modalities to visualize synergistic therapeutic effects. However, it is undeniable that the oxidizing tendency of copper under atmospheric conditions limits the preparation of copper nanoparticles. The agglomeration of copper nanoparticles may reduce the specific surface area, and the stability during catalysis is not satisfactory, which may affect the catalytic activity [17, 29]. The dose-dependent cytotoxicity may limit the application of CINMs in biomedical fields [32, 33]. All these issues need more attention in the future.

Several reviews on CINMs have been published, but few systematic and comprehensive summaries are available [34,35,36,37,38]. Considering the rapid development of CINMs in the biomedical field, we report on recent advances in photothermal-derived combination therapies of CINMs for cancer therapy, cancer imaging, and tissue regeneration in this review (Tables 1 and 2, and Fig. 1). This review begins with an overview of the classification and structure of CINMs, followed by representative studies of various CINMs-based photothermal combination therapies in cancer therapy and imaging, and a discussion of the current problems of the various therapies. The applications of CINMs-based PTT in tissue regeneration, such as skin and bone, are then summarized. Moreover, the biosafety of CINMs is discussed. Finally, the current challenges, possible solutions and future prospects for clinical translational research are considered. This review aims at elucidating the applications of PTT-derived combination therapies of CINMs in biomedicine and to encourage future designs and clinical translation.

Table 1 Applications of CINMs-based PTT in cancer therapy and imaging
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Table 2 Applications of CINMs-based PTT in tissue regeneration
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Fig. 1
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Schematic diagram of CINMs-based PTT in antitumor and tissue regeneration applications

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The classification and structure of CINMs

Many CINMs have been reported for biomedical applications, mainly including copper oxides, copper-based chalcogenides, copper nanoalloys, and copper-incorporated nanocomposites. Copper oxides include CuO and Cu2O, which are p-type semiconductor and have been widely used in batteries, gas sensors, and catalysis [65]. In the biomedical field, copper oxides can induce oxidative stress to play a tumor-killing role, and can also catalyze the generation of oxygen from endogenous hydrogen peroxide (H2O2) to alleviate tumor hypoxia [32, 146]. Ni3S2/Cu1.8S@HA possessed Z-scheme charge-transfer mechanisms that ensured high redox capacity and effective charge separation, which alleviated TME hypoxia by enabling intracellular photocatalytic O2 production and enhanced PDT. The nanocomposites had peroxidase activity that further generated more O2 to improve PDT (Fig. 5A, B).

Fig. 5
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CINMs-based PTT/PDT combination therapy. A Synthetic procedures and therapeutic mechanisms of Ni3S2/Cu1.8S@HA. B Intracellular ROS and hypoxia levels in Mda-Mb-231 cells under normal and hypoxic conditions. NC10@HA represents Ni3S2 NPs doped with 10% Cu2+. Reproduced with permission [146]. Copyright 2021, American Chemical Society. C Schematic illustration of the in vivo experiment of CuO/Cu2O TNCs against drug-resistant lung cancer. D Viabilities of H69AR cells treated with anti-EGFR-CuO/Cu2O TNCs under dark and NIR light conditions at 37 and 4 °C, respectively (**p < 0.01 and ***p < 0.001). Reproduced with permission [26]. Copyright 2021, American Chemical Society. E Synthetic procedures and therapeutic mechanisms of HCuS-TH302@PDA-Ce6/TPP NPs. F Cellular uptake and mitochondrial co-localization of HCuS@PDA-Ce6 NPs and HCuS@PDA-Ce6/TPP NPs in B6F6 cells. MTG represents Mito-Tracker Green, a mitochondrial staining dye. Reproduced with permission [142]. Copyright 2022, Springer Nature. G Synthetic procedures and therapeutic mechanisms of NP-Cu as an endogenous H2S-responsive intelligent nanoplatform. Reproduced with permission [147]. Copyright 2022, American Chemical Society

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The tissue penetration of NIR light restricts phototherapy to superficial tumors only, thus, there is the need to develop nanomaterials that can absorb longer light wavelengths to increase light penetration depth [9, 140]. Shanmugam et al. reported multifunctional CuO/Cu2O truncated nanocubes (TNCs) to treat multidrug-resistant lung tumors in deep tissues. CuO/Cu2O TNCs exhibited broad and extendable NIR absorption, as demonstrated by NIR-I (808 nm) /NIR-III (1550 nm) PTT as well as the combination of NIR-II (1064 nm) PDT and PTT (Fig. 5C, D) [26]. The extremely high molar extinction coefficient promoted tumor cell killing at a very low excitation light intensity (0.3 W·cm−2).

Ideal photosensitizers should exhibit good water solubility, stability, tumor tissue targeting ability, high quantum yield, longer wavelength absorbance, and low systemic toxicity [136]. To improve the efficacy of PDT and address the limitations of the current photosensitizers, various strategies to prevent aggregation by scaffolding uniformly dispersing photosensitizers, targeting the mitochondria, and designing activatable photosensitizers have been proposed [9, 95]. Lv et al. integrated PTT, PDT, and hypoxia-activated chemotherapy to develop a mitochondria-targeted nanoplatform (HCuS-TH302@PDA-Ce6/TPP NP) [142]. The HCuS NPs were drug carriers with good photothermal conversion properties and loaded with the thermosensitive drug (TH302) that could release the cytotoxic DNA crosslinker, bromo-isophosphoramide mustard, in the hypoxic TME. The PDA coating served as a photothermal sensitive gatekeeper to maintain HCuS NPs stability. Triphenyl phosphonium (TPP) was used to target the mitochondria, while Chlorin e6 (Ce6) acted as a photosensitizer. Therefore, NPs preferentially accumulated in the mitochondrial inner membrane to gradually activate PDT and PTT under laser irradiation at different wavelengths (660 nm and 808 nm). The generated local heat accelerated TH302 release to achieve synergistic cancer cell killing (Fig. 5E, F). This subcellular targeting strategy enhances cytotoxic activities by restricting nanomaterials to vulnerable organelles, such as lysosomes and the mitochondria, thereby preventing ROS from being consumed in the cytoplasm [39, 45, 73]. Copyright 2019, American Chemical Society. L Schematic presentation of the scheme for radiolabeling and purification of Fe3O4@Au@Cu2-xS using 64Cu. M In vitro stability of 64Cu: Fe3O4@Au@Cu2-xS in PBS and human serum at 37 °C. Reproduced with permission [159]. Copyright 2022, Wiley-VCH

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