Mesoporous platinum@copper selenide-based NIR-II photothermal agents with photothermal conversion efficiency over 80% for photoacoustic imaging and targeted cancer therapy

doi:10.1016/j.cej.2024.154172

Chemical Engineering Journal
化學工程雜誌

Volume 496, 15 September 2024, 154172
第 496 卷，2024 年 9 月 15 日，154172

https://doi.org/10.1016/j.cej.2024.154172 Get rights and content 取得權利和內容

Highlight 強調

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A mesoporous platinum@copper selenide-based NIR-II photothermal agent was prepared.
製備了介孔鉑@硒化銅基近紅外線-II光熱劑。
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This photothermal agent has the photothermal conversion efficiency over 80%.
此光熱劑的光熱轉換效率達80%以上。
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This photothermal agent was used for NIR-II photoacoustic imaging and targeted cancer therapy.
此光熱劑用於 NIR-II 光聲成像和標靶癌症治療。
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This photothermal agent provides new insights into the design of novel multifunctional biomedical nanomaterials.
這種光熱劑為新型多功能生物醫學奈米材料的設計提供了新的見解。

Abstract 抽象的

Elevating photothermal conversion efficiency (PCE) is the key to enhance curative efficacy during photothermal therapy. Nevertheless, current functionalized or synthetic methods for preparing photothermal agents with high PCE are too complicated, greatly hindering the development of photothermal therapy. In this study, we developed a tumor-targeting flower-like nanocomposite termed mesoporous platinum nanoparticles@Cu_2-_xSe-AS1411 (MPNPs@Cu_2-_xSe-AS1411, denoted as MPCSA) with remarkable PCE for high-resolution photoacoustic (PA) imaging guided photothermal/chemodynamic therapy for tumor ablation. We discovered that MPNPs served as carriers for delivering PA contrast agents. Cu_2-_xSe nanosheets emerged as promising near-infrared-II (NIR-II) PA imaging and photothermal/chemodynamic therapy agents owing to their strong localized surface plasmon resonance property in the NIR-II region. The amine-modified AS1411 aptamer, which is connected to the surface of the flower-like MPNPs@Cu_2-_xSe can target the nucleolar protein on the surface of 4T1 cells, achieving the accumulation of MPCSA at the tumor site in mice. Notably, these MPCSA nano-flowers exhibited an excellent PCE up to 82.33 % under 1064 nm laser irradiation, resulting in highly efficient cancer cell ablation and greatly hindering in vivo tumor growth. This study has paved the way for imaging-guided accurate cancer diagnosis and targeted cancer therapy.
提高光熱轉換效率（PCE）是提高光熱治療療效的關鍵。然而，目前製備高PCE光熱劑的功能化或合成方法過於複雜，大大阻礙了光熱療法的發展。在這項研究中，我們開發了一種靶向腫瘤的花狀奈米複合材料，稱為介孔鉑奈米顆粒@Cu _2- _x Se-AS1411（MPNPs@Cu _2- _x Se-AS1411，表示為MPCSA ），具有顯著的高解析度光聲PCE（ PA）成像引導光熱/化學動力學治療腫瘤消融。我們發現 MPNP 作為傳遞 PA 造影劑的載體。 Cu _2- _x Se 奈米片由於其在 NIR-II 區域具有強大的局部表面等離子體共振特性，成為有前途的近紅外線 II (NIR-II) PA 成像和光熱/化學動力學治療劑。胺修飾的AS1411適配體連接到花狀MPNPs@Cu _2- _x Se表面，可以靶向4T1細胞表面的核仁蛋白，實現MPCSA在小鼠腫瘤部位的累積。值得注意的是，這些MPCSA奈米花在1064 nm雷射照射下表現出高達82.33%的優異PCE，從而實現高效的癌細胞消融並極大地阻礙體內腫瘤生長。這項研究為影像引導的準確癌症診斷和標靶癌症治療鋪平了道路。

Graphical abstract 圖文摘要

Keywords 關鍵字

Mesoporous platinum

Copper selenide nano-flower

NIR-II photothermal agents

Photoacoustic imaging

Targeted cancer therapy

介孔鉑

硒化銅奈米花

NIR-II光熱劑

光聲成像

癌症標靶治療

1. Introduction 一、簡介

Light irradiation is a common external and remote stimulus, offering substantial advantages in curative efficacy for cancer phototherapy. NIR light-triggered photothermal therapy (PTT) has attracted considerable interest, owing to its non-invasive feature and the capability to penetrate deep tissues and ablate tumors in complex vascularized tumor microenvironment (TME) by the local heating effect [1], [2]. The utilization of NIR light as external stimulus offers simultaneous spatial and temporal control of local heating effect, thereby minimizing the harmful side effects. Localized surface plasmon resonance (LSPR) refers to the collective or coherent oscillation of free charge carrier in plasmonic material that confined at the interface [3]. Building upon the advantages of the intrinsic subwavelength characteristic of spatial profile, LSPR can accumulate the light and energy at nanomaterial scale and greatly enhance light-matter interactions, thus generating a locally increased electromagnetic field. When biological tissues, including skin, muscle, fat, and blood, are treated with NIR light, the plasmonic photothermal agents accumulated at the tumor site would undergo the light-to-heat conversion, simultaneously resulting in a rapid increase in local temperature and even hyperthermia condition, thereby ablating cancer cells and inhibiting the tumor growth. To date, the majority of the photothermal agents have been prepared to explore the first near-infrared biological window (NIR-I, 650–900 nm), exhibiting shallow tissue penetration and poor photothermal conversion efficiency (PCE) [4], [5]. For example, traditional organic photothermal materials, i.e., indocyanine green, phthalocyanine, porphyrin, and polyaniline, show insufficient PCE and severe photobleaching problem, greatly hindering their application [6]. Additionally, carbon-based photothermal nanomaterials, including carbon nanotubes [7], carbon nanodots [8], and reduced graphene oxide [9], exhibit low light absorption coefficient and require complicated synthetic and functionalized process. Compared to that of NIR-I light irradiation, the exposure under the second NIR light irradiation (NIR-II, 1000–1400 nm) can result in a higher maximum permissible exposure of skin at the power density of 1.0 W/cm². NIR-II plasmonic inorganic nanomaterials, i.e., noble metals, semiconductors, and their hybrid structure, exhibit greater potential for clinical translation compared to other photothermal agents, due to their inherent characteristics, such as excellent photostability, remarkable PCE, facile functionalization process, tunable morphology and atomic structure, adjustable water solubility, as well as superior biocompatibility [2]. Thus, it is necessary to design and construct a novel inorganic agent in combination with PTT and other tumor treatments for enhancing curative efficacy.
光照射是一種常見的外部和遠端刺激，為癌症光療的療效提供了巨大的優勢。近紅外光觸發光熱療法（PTT）因其非侵入性特徵以及能夠穿透深層組織並通過局部加熱效應在復雜的血管化腫瘤微環境（TME）中消融腫瘤的能力而引起了人們的廣泛關注[1] ， [2 ] 。利用近紅外光作為外部刺激可以同時控制局部加熱效應的空間和時間，從而最大限度地減少有害的副作用。局域表面等離子體共振（LSPR）是指限制在界面處的等離子體材料中自由載子的集體或相干振盪[3] 。利用空間輪廓固有的亞波長特性的優勢，局部表面等離子體共振可以在奈米材料尺度上累積光和能量，大大增強光與物質的相互作用，從而產生局部增強的電磁場。當皮膚、肌肉、脂肪和血液等生物組織受到近紅外線照射時，腫瘤部位累積的等離子體光熱劑會發生光熱轉換，同時導致局部溫度迅速升高，甚至導致局部溫度升高。下，從而消融癌細胞並抑制腫瘤生長。迄今為止，大多數光熱劑已製備用於探索第一個近紅外線生物窗口（NIR-I，650-900 nm），表現出淺組織穿透和較差的光熱轉換效率（PCE） [4 ] ， [5 ] 。例如，傳統的有機光熱材料吲哚菁綠、酞菁、卟啉、聚苯胺等都存在PCE不足和嚴重的光漂白問題，極大地阻礙了其應用[6] 。此外，碳基光熱奈米材料，包括碳奈米管[7] 、碳奈米點[8]和還原氧化石墨烯[9] ，光吸收係數低，需要複雜的合成和功能化過程。與NIR-I光照射相比，第二次NIR-II光照射（NIR-II，1000-1400 nm）在1.0 W/cm ²的功率密度下可導致更高的皮膚最大允許暴露量。 NIR-II等離子體無機奈米材料，即貴金屬、半導體及其雜化結構，由於其固有的特性，如優異的光穩定性、顯著的PCE、簡單的功能化過程、可調諧等，與其他光熱劑相比，表現出更大的臨床轉化潛力。因此，有必要設計和建構一種新型無機製劑，與PTT和其他腫瘤治療相結合，以提高療效。

Photoacoustic (PA) imaging is a promising biomedical imaging technique which combines the advantages of conventional optical imaging and ultrasound imaging modalities [10]. When biological tissue is under the pulsed laser irradiation, endogenous or exogenous contrast agents would convert light into heat. Subsequently, the biological tissue undergoes thermoelastic expansion and thus generates acoustic waves which can be collected through an ultrasound transducer and transformed into PA images by data processing techniques [11], [12]. In general, optimal PA contrast agents possess high tissue penetration, outstanding sensitivity, excellent photostability, superior biocompatibility, and biodegradability [13], [14], [15]. However, traditional PA imaging primarily utilizes PA contrast agents in the range of visible light (400–650 nm) or NIR-I region [16]. Biological tissues can undergo strong optical adsorption and scattering, thus resulting in shallow penetration depth and low contrast [17]. Compared to visible light and NIR-I, PA imaging in NIR-II biological window can reduce severe optical scattering on biological tissue, weaken the background signal interference, offer a strong PA signal with a up to 7-cm penetration depth and a 100-μm spatial resolution [18], exceeding the optical diffusion limit as well as the penetration depth of traditional optical imaging technique [19]. Up to now, some materials, including carbon nanotubes [20], copper sulfides/selenides [21], [22], gold nanomaterials [23], and conjugated polymers [24], have been utilized as bioactive probes for NIR-II PA imaging-guided cancer diagnosis and therapy. Nevertheless, reports on the design and construction of NIR-II PA probes with excellent targeting and therapeutic efficacy are scarce to date. Nowadays, it is crucial to develop a novel PA probe with enhanced targeting efficacy.
光聲（PA）成像是一種有前途的生物醫學成像技術，它結合了傳統光學成像和超音波成像方式的優點[10] 。當生物組織受到脈衝雷射照射時，內源性或外源性造影劑會將光轉化為熱。隨後，生物組織經歷熱彈性膨脹，從而產生聲波，聲波可以透過超音波換能器收集，並透過數據處理技術轉化為 PA 圖像[11] 、 [12] 。一般來說，最佳的PA造影劑具有高組織滲透性、出色的靈敏度、優異的光穩定性、優異的生物相容性和生物降解性[13] 、 [14] 、 [15] 。然而，傳統的PA影像主要使用可見光範圍（400-650 nm）或NIR-I區域的PA造影劑[16] 。生物組織會發生強烈的光學吸收和散射，從而導致穿透深度淺和對比度低[17] 。與可見光和NIR-I相比，NIR-II生物窗口中的PA成像可以減少生物組織上嚴重的光散射，削弱背景訊號幹擾，提供強PA訊號，穿透深度可達7厘米，穿透深度可達100-100倍。到目前為止，一些材料，包括碳奈米管[20] 、硫化銅/硒化物[21] 、 [22] 、金奈米材料[23]和共軛聚合物[24] ，已被用作NIR-II PA的生物活性探針影像引導的癌症診斷和治療。然而，迄今為止，關於具有優異靶向性和治療效果的NIR-II PA探針的設計和構建的報導還很少。如今，開發具有增強標靶功效的新型 PA 探針至關重要。

Cancer is one of the most severe diseases and a main cause of death in human beings worldwide [25]. In terms of cancer therapy, the conventional single modal treatment approach has several drawbacks, such as negligible treatment effect, poor target ability, high toxicity towards biological tissues, and vulnerability to relapse. The utilization of multimodal combination therapy can effectively solve the above-mentioned obstacles. Associated with the growth, progression, and development of cancer disease, TME plays a pivotal part in the occurrence and evolution of tumors. In comparison with normal tissue microenvironment, TME possesses some unique features in many aspects, including hypoxia [26], elevated glutathione (GSH) level [27], and low pH environment [28]. Therefore, it is pivotal to develop multimodal combined cancer treatment method to overcome the obstacles and enhance curative efficiency.
癌症是全世界人類最嚴重的疾病之一，也是人類死亡的主要原因[25] 。在癌症治療方面，傳統的單一模式治療方法有治療效果不佳、標靶性差、對生物組織毒性大、易復發等缺點。採用多模式合併治療可以有效解決上述障礙。 TME與癌症疾病的生長、進展和發展有關，在腫瘤的發生和進化中發揮關鍵作用。與正常組織微環境相比，TME在許多方面具有一些獨特的特徵，包括缺氧[26] 、穀胱甘肽（GSH）水平升高[27]和低pH環境[28] 。因此，開發多模式聯合癌症治療方法以克服障礙並提高療效至關重要。

Nowadays, chemodynamic therapy (CDT) has emerged as an effective therapeutic anticancer method based on Fenton/Fenton-like reactions. In comparison with photodynamic therapy which activates by laser irradiation to generate reactive oxygen species (ROS), CDT is a persistent cancer therapy approach which directly utilizes endogenous chemical energy to trigger ROS production under hypoxic condition [16], [29]. Multivalent transition metals, especially for iron, copper, and manganese, involve in Fenton/Fenton-like reactions which can elevate the levels of intracellular ROS in tumor tissues [30]. Specifically, high-valent transition metals (e.g., Cu²⁺, Fe³⁺, and Mn⁴⁺) possess reversible redox characteristic, thereby they can be utilized in the removal of the reducing species. Subsequently, the reduced transition metal ions can be employed in Fenton/Fenton-like reactions. It is worth noting that Cu⁺-catalyzed Fenton-like reaction can occur in a favorable reaction condition (neutral and weakly acidic condition). Cu⁺-catalyzed Fenton-like reaction exhibits a maximum rate of ·OH generation 160 times higher than that of Fe²⁺-catalyzed one, thereby it is capable of greatly enhancing the CDT effect and preventing the growth and progression of tumor tissues [31]. Therefore, it is urgent to develop a novel inorganic agent with excellent PCE and superior target ability to cancer cells for NIR-II-mediated PA imaging and PTT/CDT, which is pivotal for advancing both scientific research and clinical applications.
如今，化學動力學療法（CDT）已成為基於芬頓/類芬頓反應的有效治療抗癌方法。與透過雷射照射活化產生活性氧（ROS）的光動力療法相比，CDT是一種持久性癌症治療方法，直接利用內源性化學能在缺氧條件下觸發ROS產生[16] ， [29] 。多價過渡金屬，特別是鐵、銅和錳，參與芬頓/芬頓樣反應，可以提高腫瘤組織中細胞內ROS的含量[30] 。具體地，高價過渡金屬(例如Cu ²⁺ 、Fe ³⁺和Mn ⁴⁺ )具有可逆的氧化還原特性，因此它們可以用來去除還原物質。隨後，還原的過渡金屬離子可用於芬頓/類芬頓反應。值得注意的是，Cu ⁺催化的類芬頓反應可以在有利的反應條件（中性和弱酸性條件）下發生。 Cu ⁺催化的類 Fenton 反應最大·OH 生成速率比 Fe ²⁺催化的高 160 倍，因此能夠大大增強 CDT 效果，阻止腫瘤組織的生長和進展[31] 。因此，迫切需要開發一種具有優異PCE和對癌細胞具有優異靶向能力的新型無機製劑，用於NIR-II介導的PA成像和PTT/CDT，這對於推進科學研究和臨床應用至關重要。

In previous studies, mesoporous silica has conventionally served as a drug carrier [32]. However, compared to mesoporous silica, mesoporous platinum nanoparticle (MPNP) has been explored for biomedical applications recently. MPNP has several advantages as drug carrier [33], [34], [35], [36], including superior photothermal conversion efficiency, photothermal stability [36], and excellent biocompatibility and low cytotoxicity due to their inertia-driven reactivity in vivo and in vitro [37]. In this study, MPNP with mesoporous structure and large surface area synthesized using Pluronic F-127 (PF-127) can serve as carrier for other nanomaterials, paving the way for cancer theranostics.
在先前的研究中，介孔二氧化矽通常用作藥物載體[32] 。然而，與介孔二氧化矽相比，介孔鉑奈米顆粒（MPNP）最近已被探索用於生物醫學應用。 MPNP作為藥物載體具有多種優勢[33] 、 [34] 、 [35] 、 [36] ，包括優異的光熱轉換效率、光熱穩定性[36] ，以及由於其慣性驅動的體內反應性而具有優異的生物相容性和低細胞毒性。在這項研究中，使用Pluronic F-127（PF-127）合成的具有介孔結構和大表面積的MPNP可以作為其他奈米材料的載體，為癌症治療鋪平了道路。

The AS1411 aptamer, a G-rich quadruplex 26-mer DNA sequence, has the ability to targeting nucleolin which is overexpressed on the cell membrane of 4T1 tumor cells [38], [39]. AS1411 is one of the most advanced single-stranded DNA aptamers that has selected in clinical trials and showed selective cellular uptake towards tumor cells [40]. The AS1411 with low cytotoxicity has broad potential applications in drug delivery for cancer therapy [41], [42]. Previous studies have shown that AS1411-modified nanomaterials can specifically target 4T1 cancer cells, leading to enhanced targeting ability and therapeutic effect [43], [44], [45]. Thus, the design and application of AS1411-modified nanomaterials with superior targeting ability offers a promising avenue for developing NIR-II PA imaging-guided PTT/CDT agent.
AS1411 適體是一種富含 G 的四鏈體 26 聚體 DNA 序列，能夠靶向在 4T1 腫瘤細胞細胞膜上過度表現的核仁素[38] 、 [39] 。 AS1411是最先進的單股DNA適配體之一，已在臨床試驗中選擇並顯示對腫瘤細胞的選擇性攝取[40] 。具有低細胞毒性的AS1411在癌症治療的藥物傳遞方面具有廣泛的潛在應用[41] ， [42] 。先前的研究表明，AS1411修飾的奈米材料可以特異性靶向4T1癌細胞，從而增強靶向能力和治療效果[43] ， [44] ， [45] 。因此，具有優異標靶能力的AS1411修飾奈米材料的設計和應用為開發NIR-II PA成像引導的PTT/CDT試劑提供了有前景的途徑。

In this work, we developed a tumor-targeting flower-like nanocomposite, MPNPs@Cu_2-_xSe-AS1411 (MPCSA) with superior tumor ablation capability and excellent biocompatibility. The synthesis protocol and application of this nanocomposite is depicted in Scheme 1. The MPNPs synthesized with PF-127 possess larger specific surface area. Building upon this advantage, Cu_2-_xSe nanosheets were in-situ synthesized and self-assembled on MPNPs, yielding MPNPs@Cu_2-_xSe (MPCS) with uniform flower-like morphology. Cu_2-_xSe, an intrinsic p-type semiconductor, possesses high density of free charge-carriers and demonstrates strong LSPR in the biological NIR-II window, thereby significantly enhancing the PCE and PA imaging signal. Notably, the in vitro photothermal property study showed that MPCSA could reach 70 °C within 1 min and possessed a remarkable PCE of 82.33 % upon 1064 nm laser irradiation. Therefore, the three-dimensional MPCS nano-flowers can be readily prepared, resulting in greater specific surface area, stronger PA signal, enhanced PCE owing to MPNPs and the LSPR effect caused by the copper vacancies and higher tumor accumulation efficiency. By utilizing the AS1411-NH₂ nucleolin aptamer for targeting nucleolin on the surface of 4T1 tumor cells, MPCS conjugated with AS1411-NH₂ aptamer rapidly accumulated at the tumor site in 4T1 tumor-bearing mice. Finally, MPCSA nanocomposites were degraded into metal ions and eliminated from mice body through metabolism. Our work offers a feasible approach for enhancing the antitumor effects of MPCSA nanocomposites by integrating functionalities of NIR-II PA imaging and PTT/CDT effects.
在這項工作中，我們開發了一種腫瘤靶向花狀奈米複合材料MPNPs@Cu _2- _x Se-AS1411（MPCSA），具有卓越的腫瘤消融能力和優異的生物相容性。此奈米複合材料的合成方案與應用如方案1所示。用PF-127合成的MPNPs具有較大的比表面積。基於此優勢，Cu _2- _x Se奈米片被原位合成並在MPNPs上自組裝，產生具有均勻花狀形態的MPNPs@Cu _2- _x Se（MPCS）。 Cu _2- _x Se 是一種本徵 p 型半導體，具有高密度的自由載流子，在生物 NIR-II 視窗中表現出強局部表面等離子體共振，從而顯著增強 PCE 和 PA 成像訊號。值得注意的是，體外光熱性能研究表明，MPCSA可以在1分鐘內達到70°C，並且在1064 nm雷射照射下具有高達82.33%的PCE。因此，可以輕鬆製備三維MPCS奈米花，從而產生更大的比表面積、更強的PA訊號、MPNPs增強的PCE和銅空位引起的LSPR效應以及更高的腫瘤累積效率。透過利用AS1411-NH ₂核仁素適體標靶4T1腫瘤細胞表面的核仁素，與AS1411-NH ₂適體綴合的MPCS在4T1荷瘤小鼠的腫瘤部位快速累積。最後，MPCSA奈米複合材料被降解為金屬離子並透過代謝從小鼠體內消除。我們的工作透過整合 NIR-II PA 成像和 PTT/CDT 效應的功能，為增強 MPCSA 奈米複合材料的抗腫瘤效果提供了可行的方法。

2. Experimental section 2.實驗部分

2.1. Materials 2.1.材料

All chemicals and reagents utilized in this study were of analytical grade and utilized as received without any further purification. Polyvinylpyrrolidone (PVP), selenium dioxide (SeO₂), copper (II) chloride dihydrate (CuCl₂·2H₂O), potassium bromide (KBr), chloroplatinic acid hexahydrate (H₂PtCl₆·6H₂O), ethanol, hydrochloric acid (HCl), 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB), and 3,3′,5,5′-tetramethylbienzidine (TMB) were purchased from Aladdin Reagent Co., Ltd.. Ascorbic acid (AA) was purchased from Xilong Scientific Co., Ltd.. AS1411-NH₂-3′ was purchased from Sangon Biotech Co., Ltd.. Cell counting kit-8 (CCK-8) assay kit was procured from Solarbio Science & Technology Co., Ltd.. PF-127, Calcein-AM, propidium iodide (PI), 2-(4-amidinophenyl)-6- indolecarbamidine dihydrochloride (DAPI) and 2′,7′-dichloro-fluorescin diacetate (DCFH-DA) were procured from Beyotime Biotechnology Co., Ltd..

Type	Sequence
AS1411	5′-(GGTGGTGGTGGTTGTGGTGGTGGTGG)-3′
AS1411-NH₂-3′	5′-(GGTGGTGGTGGTTGTGGTGGTGGTGG)–NH₂-3′

本研究中使用的所有化學品和試劑均為分析級，按原樣使用，無需任何進一步純化。聚乙烯吡咯烷酮 (PVP)、二氧化硒 (SeO ₂ )、二水合氯化銅 (II) (CuCl ₂ ·2H ₂ O)、溴化鉀 (KBr)、六水合氯鉑酸 (H ₂ PtCl ₆ · 6H ₂ O)、乙醇、鹽酸抗壞血酸（HCl）、5,5'-二硫代雙（2-硝基苯甲酸）（DTNB）及3,3',5,5'-四甲基聯苯胺（ TMB）購自阿拉丁試劑_有限公司。自索拉生物科技有限公司。 ',7'-二氯螢光素二乙酸酯

(	DCFH
-	DA
₎	）

購自碧陽天生物科技有限公司。

-(GGTGGTGGTGGTTGTGGTGGTGGTGG)–NH ₂ -3′

2.2. Characterization 2.2.表徵

Transmission electron microscopy (TEM) images, elemental mapping, and size distribution were conducted on an FEI Talos 200S TEM (Thermo Fisher Scientific Inc.) with an accelerating voltage of 200 kV. The hydrodynamic diameter and Zeta potential values were recorded on a Nano Zetasizer (Malvern Panalytical Ltd.). Ultraviolet–visible-near infrared (UV–Vis–NIR) absorption spectra were recorded on an Agilent CARY 60 spectrometer (Agilent Technologies) at room temperature. The CCK-8 assay was tested by an EL800 microplate reader (Bio Tek instruments). X-ray photoelectron spectrometer (XPS) results were obtained by an ESCALAB 250Xi XPS (Thermo Fisher Scientific Inc.). Powder X-ray diffraction (XRD) patterns were measured by Rigaku D/max 2500/pc diffractometer (Rigaku) with Cu Kα radiation (λ = 1.5406 Å). Confocal cell imaging was implemented on a Zeiss LSM710 laser scanning microscope (Carl Zeiss AG). Both in vitro and in vivo NIR-II photothermal performance was examined by an infrared thermal imaging camera (Optris Infrared Sensing, Portsmouth) with a 1064-nm laser. Multispectral Optoacoustic Tomography (MSOT) was recorded via the inVision 256-TF imaging system (iThera Medical GmbH).
透射電子顯微鏡 (TEM) 影像、元素分佈和尺寸分佈在 FEI Talos 200S TEM (Thermo Fisher Scientific Inc.) 上進行，加速電壓為 200 kV。流體動力學直徑和 Zeta 電位值在 Nano Zetasizer（Malvern Panalytical Ltd.）上記錄。紫外-可見光-近紅外線 (UV-Vis-NIR) 吸收光譜在室溫下使用 Agilent CARY 60 光譜儀（Agilent Technologies）記錄。 CCK-8 測定透過 EL800 酶標儀（Bio Tek 儀器）進行測試。 X 射線光電子能譜儀 (XPS) 結果透過 ESCALAB 250Xi XPS (Thermo Fisher Scientific Inc.) 獲得。粉末 X 射線衍射 (XRD) 圖案由 Rigaku D/max 2500/pc 衍射儀 (Rigaku) 使用 Cu Kα 輻射 (λ = 1.5406 Å) 測量。共焦細胞成像在 Zeiss LSM710 雷射掃描顯微鏡（Carl Zeiss AG）上進行。體外和體內NIR-II 光熱性能均透過紅外線熱成像相機（Optris Infrared Sensing，朴茨茅斯）和 1064 nm 雷射進行檢查。多光譜光聲斷層掃描 (MSOT)透過inVision 256-TF 影像系統 (iThera Medical GmbH) 進行記錄。

2.3. Synthesis of MPNPs 2.3. MPNPs的合成

In this work, the MPNPs were obtained via a wet-chemical approach. In a typical experiment, KBr (2,000 mg), PF-127 (900 mg), and AA (0.1 mol/L, 30 mL) were sequentially added into 25 mL of deionized water followed with sonication. Subsequently, H₂PtCl₆·6H₂O (0.2 mol/L, 1.5 mL) was introduced into the above-mentioned seed solution, which was then kept undisturbed at 70 °C for 15 h. The as-synthesized Pt nanoparticles were collected by centrifugation (8,000 rpm, 10 min), washed thrice with ethanol, and re-dispersed in a mixture of ethanol (100 mL) and HCl (200 μL). Afterwards, the PF-127 surfactant removal from the surface of Pt nanoparticles was carried out under magnetically stirring (500 rpm) at 60 °C for 3 h. Finally, the MPNPs were obtained through centrifugation (8,000 rpm, 10 min), washed thrice with ethanol, and re-dispersed in 40 mL of ethanol.
在這項工作中，MPNP 是透過濕化學方法獲得的。在典型實驗中，將 KBr (2,000 mg)、PF-127 (900 mg) 和 AA (0.1 mol/L，30 mL) 依序加入 25 mL 去離子水中，然後進行超音波處理。隨後，將H ₂ PtCl ₆ ·6H ₂ O（0.2 mol/L，1.5 mL）引入上述種子溶液中，然後在70 ℃下靜置15 h。透過離心（8,000 rpm，10 分鐘）收集合成的 Pt 奈米顆粒，用乙醇洗滌三次，並重新分散在乙醇（100 mL）和 HCl（200 μL）的混合物中。然後，在60℃下以磁力攪拌（500rpm）3小時，從Pt奈米粒子表面移除PF-127界面活性劑。最後，以離心（8,000 rpm，10 min）獲得MPNP，以乙醇洗滌三次，重新分散於40 mL乙醇中。

2.4. In-situ synthesis of Cu_2-xSe on MPNPs
2.4. MPNPs上Cu _{2- x} Se 的原位合成

Prior to the growth of Cu_2-_xSe, the synthesized MPNPs underwent centrifugation (8,000 rpm, 10 min), washed thrice with deionized water, and then re-dispersed in 7 mL of deionized water, followed by sonication for several minutes. For the in-situ synthesis of Cu_2-_xSe on MPNPs, PVP (1.2 g) was dissolved in 135 mL of deionized water. Subsequently, 1.5 mL of as-prepared MPNP solution was added to the PVP aqueous solution, and the mixed solution was magnetically stirred for 5 min. Then, AA (0.4 mol/L, 6 mL) and SeO₂ (5.6 mmol/L, 1.2 mL) were added successively to the mixed solution and stirred for 5 min. Further, AA (0.4 mol/L, 12 mL) and CuCl₂·2H₂O (11.2 mmol/L, 1.2 mL) were added to the mixture, followed by stirring for 48 h at room temperature. Last, the final products were collected using centrifugation (12,000 rpm, 12 min) and washed three times with deionized water. Under vacuum condition, the MPCS samples were dried overnight at 60 °C.
在生長 Cu _2- _x Se 之前，將合成的 MPNP 離心（8,000 rpm，10 分鐘），用去離子水洗滌三次，然後重新分散在 7 mL 去離子水中，然後超音波處理幾分鐘。為了在 MPNP 上原位合成 Cu _2- _x Se，將 PVP (1.2 g) 溶解在 135 mL 去離子水中。隨後，將1.5mL製備好的MPNP溶液加入PVP水溶液中，並將混合溶液以磁力攪拌5分鐘。然後，將AA(0.4mol/L，6mL)和SeO ₂ (5.6mmol/L，1.2mL)依序加入混合溶液中並攪拌5分鐘。此外，將AA(0.4mol/L，12mL)和CuCl ₂ ·2H ₂ O(11.2mmol/L，1.2mL)加入混合物中，然後在室溫下攪拌48小時。最後，透過離心（12,000rpm，12分鐘）收集最終產物，並用去離子水洗滌3次。在真空條件下，MPCS 樣品在 60 °C 下乾燥過夜。

2.5. Synthesis of MPCSA nanocomposites
2.5. MPCSA奈米複合材料的合成

In a typical procedure, MPCS (0.05 g) were dissolved in 6 mL of deionized water. Subsequently, AS1411-NH₂-3′ (100 μmol/L, 0.4 mL) was added and shaken at 1,500 rpm for 24 h at room temperature. The final products were collected using centrifugation (12,000 rpm, 15 min) and washed trice with deionized water. The MPCSA were further dried under a freeze-drying process.
在典型程序中，將 MPCS (0.05 g) 溶解在 6 mL 去離子水中。隨後，加入AS1411-NH ₂ -3'(100 μmol/L，0.4 mL)，並在室溫下以1,500 rpm振盪24 h。使用離心（12,000rpm，15分鐘）收集最終產物並用去離子水洗滌三次。 MPCSA 在冷凍乾燥過程中進一步乾燥。

2.6. Peroxidase (POD)-mimic activity of MPCSA
2.6。 MPCSA 的過氧化物酶 (POD) 模擬活性

TMB (0.5 mM) was employed as a ROS indicator to measure the POD-mimic activity of MPCSA under the existence of H₂O₂. Then, the absorbance values of the mixture and the MPCSA only solution were recorded via a UV–Vis absorption spectroscopy.
採用 TMB (0.5 mM) 作為 ROS 指示劑來測量 H ₂ O ₂存在下 MPCSA 的 POD 模擬活性。然後，透過紫外-可見光吸收光譜記錄混合物和僅 MPCSA 溶液的吸光度值。

2.7. GSH depletion with MPCSA nanocomposites
2.7. MPCSA 奈米複合材料去除 GSH

The levels of GSH and its oxidative form, glutathione disulfide (GSSG), were measured using Ellman’s assay. In this assay, DTNB, a commercial Ellman reagent, can break the disulfide bond (-S-S-) in GSH, generating another compound, 2-nitro-5-thiobenzoate acid [46]. In details, 400 μg/mL of MPCSA was added to a solution containing 10 mM GSH at room temperature. Subsequently, 0.25 mM DTNB was introduced into the mixed solution to indicate the sulfhydryl (SH) groups in GSH. The differences of the absorbance intensity at 326 nm and 412 nm were tested on 0, 0.5, 1, 1.5, 2, 3, 4, and 5 h via UV–Vis spectrophotometer.

2.8. Cell culture and cytotoxicity assessment

Human normal liver HL-7702 cells and murine breast cancer 4T1 cells were cultured by using Dulbecco’s modified Eagle’s medium (DMEM) and Roswell Park Memorial Institute (RPMI) 1640 medium, respectively. Both media contained 10 % fetal bovine serum (FBS) and 1 % penicillin/streptomycin. The HL-7702 and 4T1 cells were maintained in incubators at 37 °C with 5 % CO₂.

For the CCK-8 assay, cells were seeded in 96-well plates at a cell density of 1 × 10⁴ per well and then incubated at 37 °C with 5 % CO₂ for 24 h. Afterwards, the corresponding media solutions of MPCSA at varying concentrations from 0 to 400 μg/mL were added to the well plates containing 4T1 and HL-7702 cells, respectively. After another 24-h incubation period, cell viability was determined by standard CCK-8 assay and then tested by a Microplate Reader via a 450 nm absorbance.

2.9. In vitro targeting ability of MPCSA to 4T1 cancer cells

To investigate the targeting ability of MPCSA with the AS1411-NH₂ aptamer towards cancer cells, Cy5 fluorophore was conjugated to AS1411-NH₂. HL-7702 and 4T1 cells were incubated in confocal culture dishes at a cell density of 1 × 10⁵ per dish for 24 h. Subsequently, two types of cells were incubated with 400 μg/mL of MPCSA. After 0.5-h incubation, two types of cells were washed thrice with phosphate-buffered saline (PBS) solution and observed with a confocal cell imaging microscopy.

2.10. Detection of intracellular hydroxyl radicals

The generation of intracellular •OH was indicated by the commercial fluorescent probe DCFH-DA under confocal cell imaging microscopy. The 4T1 cells were first incubated in four confocal culture dishes at a cell density of 1 × 10⁵ per dish for 24 h. After rinsing twice with PBS solution, 4T1 cells were incubated for 12 h with 400 μg/mL of MPCSA, followed by rinsing twice with PBS solution. Next, 200 μL of the RPMI 1640 medium was added to each dish. Specifically, 4T1 cells were subjected to various treatments: 1) Control, 2) PBS+Laser, 3) MPCSA, and 4) MPCSA+Laser. Cells treated with PBS and MPCSA were treated with 1064 nm-laser exposure at 1.0 W/cm² for 1 min, respectively. Afterwards, four groups of cells were incubated with DAPI and DCFH-DA fluorescent probe for 30 min. After rinsing with PBS solution, the excess DAPI and DCFH-DA was removed and then treated cells were then analyzed under fluorescence imaging.

2.11. Animal model and animal ethics

Female BALB/C mice, 8 weeks old, were procured from the Experimental Animal Center at the Shanghai Institute of Planned Parenthood Research. All mice were raised under specific pathogen-free condition with ad libitum access to water and standard chow diet. Animal handling protocols were approved by the Animal Ethics Committee of Guangxi Normal University (Approval No.: GXNU-202310–001). All animal studies were conducted at the Laboratory Animal Center of Guangxi Normal University, which were in line with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All BALB/C female mice were randomly allocated into four groups, each comprising five mice. A 100 μL suspension of 4T1 cells (1 × 10⁶ cells) was subcutaneously inoculated into the right hind leg of anesthetized nude mice.

2.12. In vitro and in vivo PA imaging

MSOT inVision 256-TF small animal scanner was employed for PA imaging and data collection. For in vitro PA assays, MPCSA at varying concentrations from 0 to 500 μg/mL were added into corresponding 6 mm plastic tubes. For in vivo PA assays, the 4T1 tumor-bearing mouse was anesthetized with isoflurane through nose cone and then positioned in the chamber of the MSOT scanner. In vivo PA assays were acquired at a scan step of 0.3 mm at different time points post-injection of MPCSA (0, 1, 2, 4, 6, 8, 20, and 24 h). Subsequently, PA image reconstruction was performed using the standard back projection algorithm.

2.13. In vitro photothermal performance of MPCSA

To assess the in vitro photothermal effect of MPCSA, 4T1 and HL-7702 cells were seeded and incubated for 24 h at 37 °C in 5 % CO₂ and then conducted CCK-8 assay to measure cell viability. Cell damage after PTT was investigated using confocal laser scanning microscopy (CLSM). Specifically, cells were pre-treated with the following conditions: 1) Control, 2) PBS+Laser, 3) 400 μg/mL MPCSA in RPMI 1640 and DMEM medium, respectively, and 4) 400 μg/mL MPCSA in RPMI 1640 and DMEM medium + Laser (1064 nm laser irradiation, 1 W/cm², 5 min), respectively. After laser irradiation, the 4T1 and HL-7702 cells were co-stained by PI (red fluorescence, dead cells) and Calcein-AM (green fluorescence, live cells) for 20 min at 37 °C in 5 % CO₂ before CLSM analysis.

To investigate the intrinsic photothermal property of MPCSA, PBS solution and MPCSA at various concentrations (100, 200, and 400 µg/mL) were treated with 1064 nm laser irradiation (1 W/cm², 1 min). The photothermal stability of MPCSA at 400 µg/mL was evaluated by three consecutive heating and cooling cycles, with laser irradiation on for 1 min and then off for 5 min cooling period during one complete cycle.

2.14. Evaluation of the photothermal therapeutic effect of MPCSA

Twenty tumor-bearing female BALB/C mice were evenly divided into four groups (n = 5 in each group) to evaluate the in vivo synergistic photothermal/chemodynamic therapeutic effect of MPCSA. In the first group (control group), 100 μL of the PBS solution was intravenously injected into the tail veil of the mice. In the second group, 1064-nm laser irradiation (1 W/cm², 5 min) were carried out on the mice only. In the third group, 100 μL of the MPCSA solution was intravenously injected into the tail veil of the mice. In the fourth group, 100 μL of the MPCSA solution was intravenously injected into the tail veil of mice, and after 4 h, the mice were treated upon 1064-nm laser irradiation (1 W/cm², 5 min). Tumor temperature and thermographic images were collected through the Optris PI infrared camera. After each treatment, the tumor volume (V) was measured through an electronic caliper and determined by the below-mentioned equation: V=a × b² × 0.5, in which a is the longest diameter and b is the shortest diameter orthogonal to a. The therapeutic effect was determined by monitoring the relative mean tumor volume (V/V₀), in which the initial tumor size at Day 0 was denoted as V₀.

2.15. Histological examination

At Day 16, mice in all groups were euthanized by cervical dislocation. The major organs (lung, liver, spleen, kidney, and heart) and tumor tissues were collected from the above 4 groups of mice after 16 days for subsequent histological analysis. The major organs of the mice were stained with hematoxylin and eosin (H&E).

2.16. Statistical analysis

All data were illustrated as mean ± standard deviation (n ≥ 3). Origin 2021 and GraphPad Prism 8.0 Software were utilized for statistical evaluation. Statistically significant difference was evaluated through Student’s t test. The p-value < 0.05 can be considered statistically significant.

3. Results and discussion

3.1. Synthesis and characterizations of MPCSA

The TEM image (Fig. 1a) revealed that MPNPs capped by PF-127 were homogeneously distributed. The MPNPs possessed distinct mesoporous structure with a particle size of 40–50 nm. As shown in Fig. 1b, the as-synthesized Cu_2-_xSe nanosheets exhibited an average lateral size of 20 nm. MPCS nano-flowers were constructed by the in-situ growth of Cu_2-_xSe on the as-synthesized MPNPs, resulting in superior surface-area-to-mass ratio. Next, the aptamer AS1411-NH₂-3′ was added into MPCS, and –NH₂ was conjugated to MPNPs via coordinate bond. Thus, MPCSA nanocomposites with unique three-dimensional flower-like structures were successfully synthesized (see Experimental 2.3 Synthesis of MPNPs, 2.4 , 2.5 Synthesis of MPCSA nanocomposites). Several Cu_2-_xSe nanosheets were absorbed on a single MPNP, which increased the surface area of MPCSA (Fig. 1c). Moreover, the energy-dispersive X-ray spectroscopy (EDS) elemental mapping measurements of MPCSA (Fig. 1d–h) confirmed that Cu_2-_xSe nanosheets were uniformly grown on the MPNPs. As displayed in Fig. 1i, the size distribution histogram of MPCSA revealed that the as-synthesized material possessed an average size of 86.6 ± 2.3 nm. In Fig. S1, the average hydrodiamater was measured to be 93.0 nm. Subsequently, the stability of MPCSA nanocomposites in different physiological media were studied. The experimental results show that MPCSA displayed great physiological stability in water, PBS solution, and RPMI 1640 + 10 % FBS (Fig. S2).

In Fig. 2a, the difference between UV–Vis–NIR spectra of MPNPs and MPCSA confirmed the successful growth of Cu_2-_xSe on MPNPs, since Cu_2-_xSe exhibited strong absorption peak in NIR-II window [30]. In Fig. 2b, the absorbance of MPCSA in the NIR-II region enhanced along with the increased concentration of MPCSA. Building upon the UV–Vis–NIR spectra of MPCSA at different concentration, there exists a linear relationship between MPCSA concentration and absorbance intensity at 1064 nm (Fig. S3) [47]. Powder XRD patterns of MPNPs, Cu_2-_xSe, and MPCSA were depicted in Fig. 2c. All diffraction peaks of MPNPs can be indexed to face-centered cubic Pt nanoparticles (JCPDS No.87–0636). Moreover, all diffractions peaks of MPCSA were consistent with those of MPNPs and Cu_2-_xSe, confirming the successful construction of MPCSA. In Fig. S4, the average Zeta potential of MPNPs was −7.83 ± 0.17 mV. After Cu_2-_xSe nanoflake was synthesized in situ, the Zeta potential of MPCS raised to −0.23 ± 0.14 mV, which was attributed to the positively charged Cu_2-_xSe nanoflakes. Then, the average Zeta potential of MPCSA reversed back to −12.03 ± 0.23 mV, confirming the successful functionalization of the negatively charged aptamer AS1411-NH₂ [48].

The XPS results revealed the valence states of Pt, Cu, and Se in the as-synthesized MPCSA nanocomposites (Fig. 2d). The high-resolution XPS profile of MPCSA in Pt 4f region where peaks were positioned at 74.28 eV and 72.18 eV and binding energy of Pt was accordance with previous study (Fig. 2e) [49]. As illustrated in Fig. 2f, the high-resolution XPS profile of MPCSA nanocomposites in the Cu 2p region can be deconvoluted into Cu 2p_1/2 and Cu 2p_3/2, which was consistent with previous research [50]. Specifically, two peaks for the Cu 2p_1/2 signal at 954.48 and 952.28 eV attributed to the electron energy peaks of Cu²⁺ and Cu⁺, respectively. The other two peaks for the Cu 2p_3/2 signal at 932.9 and 934.7 eV attributed to the electron energy peaks of Cu²⁺ and that of Cu⁺, respectively. In Fig. 2g, the peaks at 55.28 and 54.18 eV corresponded to the peaks of Se 3d_5/2 and 3d_3/2, respectively, which was in line with a previous study [46]. Thus, the high-resolution XPS profiles of MPCSA in the Cu 2p and Se 3d regions confirmed the successful synthesis of Cu_2-_xSe.

3.2. Biocompatibility of MPCSA

Excellent biocompatibility is one of the key criteria for choosing photothermal agents. Herein, the standard CCK-8 assay was selected to evaluate the cytotoxicity of MPCSA. As demonstrated in Fig. 3a, the cell viability was greater than 80 % for both murine cancer cells (4T1) and normal human liver cells (HL-7702) after incubating with the MPCSA nanocomposites at varying concentrations from 0 to 400 μg/mL for 24 h, indicating its good biocompatibility and low cytotoxicity. Similarly, the cell viability was measured for both 4T1 and HL-7701 cells by 1064 nm laser irradiation (1.0 W/cm², 5 min) after incubation with MPCSA at 400 μg/mL. The results showed that the laser irradiation treatment effectively killed 4T1 cells. The three remaining groups of HL-7702 and 4T1 cells were subjected to the following treatments: 1, Control; 2, PBS+Laser; and 3, MPCSA. The results showed that nearly all 4T1 cancer cells were killed after the NIR-II photothermal treatment (Fig. 3b).

Before conducting in vivo tumor therapy, hemolysis assay was conducted to measure the hemolytic activity and biocompatibility of MPCSA by investigating their effects on erythrocytes. The experimental results revealed that the supernatant of water (the positive control) was light red, whereas the supernatants of the MPCSA solution and saline solution (the negative control) were colorless and transparent, indicating that the hemolytic effect of the MPCSA was nearly negligible (Fig. S5). As the concentration of MPCSA raised, the rate of erythrocyte hemolysis increased slightly. Notably, the maximum hemolysis rate of MPCSA was 3.67 % when its concentration reached 500 μg/mL, which was below the permissible limit of 5 %, confirming the biocompatibility of MPCSA nanocomposites [51].

The Cy5 fluorophore was modified on the AS1411-NH₂ aptamer to investigate the targeting ability of MPCS nano-flowers with Cy5-AS1411-NH₂. 4T1 and HL-7702 cells were incubated with MPCSA for 0.5 h and observed under a CLSM (Fig. 3c). The 4T1 cells treated with MPCSA showed different red fluorescence under the excitation wavelength (λ_ex = 638 nm), where the red fluorescence was the emitted signal by Cy5. As depicted in scheme (Fig. 3h), the Cy5-AS1411-NH₂ aptamer conjugated with MPCS nano-flowers targets the overexpressed nucleolar proteins on 4T1 cellular membrane. As shown in Fig. 3g, the quantified results corroborated that the mean fluorescence intensity of Cy5 on 4T1 cells was 74.06 times stronger than that on HL-7702 cells after a 0.5-h incubation. Thus, MPCSA can access through the cell membrane and reach the cytoplasm of 4T1 tumor cells (Fig. S6), proving that the as-prepared MPCSA nano-flowers manifested high binding affinity to 4T1 tumor cells.

Next, fluorescence microscopy analysis further confirmed the obvious 4T1 cell death after NIR-II photothermal treatment. Different groups of cancer cells were pre-treated, followed by co-staining with Calcein-AM and PI for 20 min before fluorescence microscopy analysis. After the 1064 nm laser irradiation treatment, the live (green) and dead (red) cells show obvious color differences from the co-stained cells. 4T1 and HL-7702 cells were evenly divided into four groups (control, ‘PBS+Laser’, MPCSA, and ‘MPCSA+Laser’). More than 95 % of 4T1 cells treated with MPCSA incubation and 1064 nm laser irradiation were killed, whereas nearly no 4T1 or HL-7702 cells were killed in the remaining three groups (Fig. 3d). As illustrated in Fig. 3f, the quantified results in bar charts elaborated that the mean fluorescence intensity of PI (red fluorescence) treated with ‘MPCSA+Laser’ in 4T1 cells was 5.87 times stronger than that treated with MPCSA. The above experimental results indicated that MPCSA had strong phototherapeutic effect at the cellular level owing to the in-situ synthesis of Cu_2-_xSe, a superior NIR-II photothermal agent, on MPNPs. Besides, Cy5-AS1411-NH₂ connected with MPNPs in MPCSA exhibited precise targeting ability for 4T1 cancer cells, thus resulting in negligible harmful effect on HL-7702 normal cells. The Calcein-AM/PI cell viability assay by the fluorescence images was consistent with the CCK-8 assay results. Thus, flower-like biocompatible MPCSA nanocomposites showed potential applications in breast cancer therapy.

3.3. NIR-II plasmon-enhanced •OH generation

As illustrated in Fig. 4a, free Cu⁺ ions in the MPCSA nanocomposites can react with H₂O₂ in the Fenton-like reaction to form •OH radicals, resulting in the activation of CDT. To verify this mechanism, TMB was employed as indicators to demonstrate the formation process of •OH radicals in the cascade reaction via UV–Vis absorption spectroscopy. In Fig. 4b, the experimental results demonstrated that the color of the TMB solution turned light blue and its absorbance intensity increased when H₂O₂ was added into MPCSA. It suggests that the generation of •OH radical was owing to the reaction between free Cu⁺ ions in the MPCSA nanocomposites and H₂O₂ solution. While in control experiment, the TMB solution remained colorless in the absence of the H₂O₂ solution.

In previous study, it was reported that GSH can undergo a redox process in the presence of Cu²⁺ and convert into its oxidative GSSG species [46]. The GSH depletion was verified by the Ellman’s assay. In this assay, DTNB was employed to cause the breakage of the disulfide bond (-S-S-) and generation of a compound, termed 2-nitro-5-thiobenzoate acid. The time-dependent absorption spectra indicating the concentration levels of GSH and GSSG were measured via UV–Vis absorption spectroscopy. Fig. 4c elaborates that the absorbance intensity of DTNB decreased at 412 nm while the absorbance intensity of 2-nitro-5-thiobenzoate acid increased at 326 nm, suggesting GSH was gradually depleted and meanwhile GSSG was generated with the prolongation of the reaction period, respectively. Therefore, the MPCSA nanocomposites can efficiently deplete the GSH, ascribing to the existence of free Cu²⁺ ions in MPCSA.

Furthermore, the intracellular •OH radical generation was measured by the commercial fluorescent probe DCFH-DA [52], [53]. As depicted in Fig. 4e, compared with those treated with MPCSA under dark condition, 4T1 cells treated with MPCSA+1064 nm laser (1 W/cm², 1 min) showed significantly greater fluorescence intensity ascribing to the oxidation of DCFH-DA fluorescent probe by the extra •OH radicals. Notably, negligible green fluorescence was detected in the 4T1 cells treated with either PBS under dark condition or PBS upon laser irradiation. The corresponding mean fluorescence intensities of Fig. 4e were quantified in bar charts (Fig. 4d). The green fluorescence intensity of ‘MPCSA+Laser’-treated 4T1 cells was 1.4 times stronger than that of MPCSA group, suggesting that the photothermal-enhanced POD-like catalytic activity accelerates the generation of ·OH radicals. Therefore, owing to the extra •OH production through Cu⁺-catalyzed Fenton-like reaction, efficient depletion of GSH and formation of intracellular Cu⁺ over time, MPCSA can serve as a potentially effective PTT/CDT agent for cancer therapy.

3.4. In vitro photothermal properties of MPCSA and in vivo photothermal-enhanced CDT for tumors

To investigate the photothermal properties of the MPCSA nanocomposite, the temperature of pure PBS and MPCSA solution at different concentrations (100, 200, and 400 μg/mL) was monitored upon 1064 nm laser irradiation (Fig. 5a). As shown in Fig. 5b and c, at a power density of 1.0 W/cm², no significant changes were observed in the temperature of pure water (the control group). Nevertheless, the speed of temperature changes of MPCSA solution gradually went up as the concentration of MPCSA increased from 100 to 400 μg/mL. At 400 μg/mL, the temperature of the MPCSA solution reached up to 70 °C within 1 min, suggesting the superior photothermal property of MPCSA that can efficiently convert NIR light into heat. The enhanced PCE can be attributed to the MPNPs and strong LSPR effect caused by the copper vacancies of the self-assembled Cu_2-_xSe nano-flowers upon NIR-II laser irradiation. To further test the thermal stability of MPCSA, the photothermal responses of 400 µg/mL MPCSA solution were recorded for three consecutive on/off cycles upon 1064 nm laser irradiation (1 W/cm²) (Fig. 5d). Specifically, the temperature was first going up for 1 min (1064 nm laser on) and then cooling down to room temperature for 5 min (1064 nm laser off). It is worth mentioning that the photothermal properties were kept by the MPCSA nano-flowers during the consecutive heating–cooling cycles, thereby proving the excellent physicochemical and photothermal stability of MPCSA.

Subsequently, to quantify the photothermal transduction efficiency, the experimental data were processed based on a method that was first reported by Roper and his co-workers in 2007 [54]. The calculation process and equations were provided in Supporting Information. Specifically, the associated time constant τ values were determined by linear fitting between time and −ln(θ). τ values of MPCSA and PBS solution were calculated to be 113.6508 s (Fig. 5e) and 274.3863 s (Fig. S7), respectively. Therefore, the PCE (

η

) of MPCSA at 1064 nm was determined to be 82.33 %, which was among the highest for Cu_2-_xSe-based photothermal agents and even rivals those of plasmonic noble metal materials, i.e., Au and Ag. The representative NIR-II absorbing inorganic materials and their corresponding PCE were summarized in Table S1.

Based on the superior in vitro NIR-II photothermal properties of MPCSA, the in vivo photothermal effect of MPCSA was further examined. The same volumes of MPCSA and PBS solutions were intravenously injected into the tail vein of 4T1 tumor-bearing mice. After 4-h injection, the tumor site was treated by 1064 nm laser irradiation (1.0 W/cm², 5 min). An infrared thermal imaging camera was utilized to record the infrared thermal images at various time points (Fig. 5f) and the corresponding temperature readouts (Fig. 5g), demonstrating the superior in vivo photothermal effect of MPCSA over PBS. The temperature of the tumor tissue treated with MPCSA+laser rapidly increased from 29.5 °C to 59.8 °C within 5 min, thereby efficiently ablating tumor cells in vivo. In the control group, the temperature of the tumor tissue which treated with ‘PBS+Laser’ experienced a slight increase to 36.0 °C, resulting in a negligible tumor-ablating effect. Overall, the in vitro and in vivo experimental results prove that the MPCSA nano-flowers not only possess good photothermal stability but also show outstanding tissue penetration ability, making it a promising NIR-II phototherapeutic agent for tumor treatment.

3.5. NIR-II guided in vitro and in vivo PA imaging of MPCSA

Fig. 6a and b illustrated the NIR-II PA signals of the MPCSA solution at different concentrations upon 1064 nm laser irradiation. As demonstrated in Fig. 6c, the PA signal intensity exhibited a positive linear relationship with MPCSA solution concentration, due to strong NIR-II LSPR absorption of Cu_2-xSe [30]. The linear regression equation was

I = 2.42 + 113.71 C_{MPCSA}

R^{2} = 0.999

. These findings suggest that the in-situ synthesis of Cu_2-xSe on MPNPs achieves modified and enhanced photothermal and PA imaging properties on the novel flower-like MPCSA nanocomposite, which can act as a superior NIR-II PA imaging agent.

Because MPCSA showed suitable biocompatibility and superior in vitro performance of NIR-II PA imaging, it was further employed as a probe for precise imaging of tumor tissues in 4T1-tumor-bearing mice by PA imaging technique in the NIR-II region. The MPCSA solution (8 mg/kg) was intravenous injected, consequently followed by PA imaging under 1064 nm laser irradiation at varying time points (0, 1, 2, 4, 6, 8, 20, and 24 h) after intravenous injection (Fig. 6d). Notably, the PA imaging of the 4T1 tumor-bearing mice before MPCSA injection was selected as the control group; the PA intensity at the tumor site was relatively low in this group compared with the experimental groups, confirming the absence of background interference from other in vivo biological tissues. In Fig. 6e, as time progressed, the PA intensity first gradually increased and then gradually decreased. Owing to AS1411-NH₂ accumulation via tissue permeation, the strongest PA signal was observed 4 h after injecting MPCSA. Thereafter, PA intensity gradually decreased and returned to the normal level at 24 h, indicating the biodegradability of MPCSA in tumor tissues. The above results further prove that MPCSA nanocomposite is an ideal PA imaging nanoprobe for accurately imaging tumor sites in the NIR-II region.

3.6. PTT effect of MPCSA for targeting in vivo tumor ablation

Based on the desirable in vitro PTT effect of MPCSA, the synergistic curative effect of MPCSA nanocomposites for tumor ablation was then explored in vivo (Fig. 7a). Guided by the NIR-II PA imaging results of 4T1 tumor-bearing mice, the photothermal therapeutic effect of MPCSA solution (8 mg/kg) was assessed by recording the tumor volume and body weight of the four experimental groups (twenty mice in total). Building upon the PA imaging results illustrated in Fig. 6d, laser irradiation was performed at 4 h after the tail vein injection of PBS or MPCSA for the ‘PBS+Laser’ or ‘MPCSA+Laser’ group, respectively. Fig. 7b was the digital images of four groups of mice taken at the 0, 8th, and 16th day. As shown in Fig. 7c, for the ‘MPCSA+Laser’ group, the tumor was effectively ablated at 8th day and did not regrow after laser irradiation (1064 nm, 1.0 W/cm², 5 min). In contrast, for the

MPCSA group without laser treatment, only partial tumor ablation was observed. Furthermore, the relative tumor volumes of the other two groups (Control and ‘PBS+Laser’) showed similar tumor growth rates during the 16 days, suggesting no distinct inhibition effect on tumor growth. In contrast to the observations in the three other groups, the trend curve of relative tumor volume for the ‘MPCSA+Laser’ group clearly illustrated the outstanding tumor ablation effect due to the photothermal effect of the MPCSA nanocomposites upon 1064 nm laser irradiation. After 16 days, the tumors were collected from all groups of mice body and their sizes were consistent with tumor volume changes (Fig. 7d). Notably, as demonstrated in Fig. 7e, no obvious body weight loss was observed in the four groups of mice during the last 16 days under photothermal treatment, indicating no obvious organism toxicity of the MPCSA. On Day 16, the major organs and tumor tissues were dissected from the mice for further analysis. H&E staining pictures of major organs (heart, liver, spleen, lung, and kidney) were recorded to assess the biosafety of the as-synthesized MPCSA after the photothermal treatments of all the groups for 16 days. As demonstrated in Fig. 7f, all of the groups showed negligible histopathological abnormalities or lesions, proving the biocompatible property of nanocomposites and the doses of nanocomposites used herein were within the safe range. These in vivo experimental results demonstrate that MPCSA is an effective and biocompatible PTT/CDT therapeutic agent in accurate diagnosis and efficient therapy for tumor treatment.

4. Conclusion

In summary, we have prepared MPCSA nano-flowers with superior PCE and targeting ability to 4T1 cancer cells and strong adsorption in NIR-II window and conducted systematic studies on MPCSA. Notably, the PCE of MPCSA nano-flowers can reach up to 82.33 %, which is even comparable to that of plasmonic noble metal materials. Furthermore, the experimental results revealed that the MPCSA nano-flowers had intrinsic NIR-II PA imaging properties with non-invasive imaging mode and high spatial resolution in vivo. The MPCSA nano-flowers with good biocompatibility and negligible harmful effect in 4T1 tumor-bearing mice can be an efficient candidate for PA imaging-guided PTT/CDT both in vitro for killing cancer cells and in vivo for ablating tumors under 1064 nm laser irradiation. Therefore, this study put forward a facile strategy to construct novel multifunctional biomedical nanomaterials with great potential in precise diagnosis and efficient cancer treatment.

CRediT authorship contribution statement

Jinzhe Liang: Writing – original draft, Methodology, Investigation, Conceptualization. Yanting Yang: Writing – original draft, Methodology, Investigation, Data curation. Yanni Luo: Investigation, Formal analysis, Data curation. Lixian Huang: Investigation, Formal analysis, Data curation. Shulin Zhao: Writing – review & editing, Writing – original draft, Resources, Methodology, Funding acquisition, Conceptualization.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgments

This work was supported by Natural Science Foundation of China (No. 22174026) and BAGUI Scholar Program.

Appendix A. Supplementary data

The following are the Supplementary data to this article:Download: Download Word document (855KB)

Supplementary Data 1.

Data availability

The authors do not have permission to share data.

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Cited by (1)

A hydrogen sulfide-activated Pd@Cu<inf>2</inf>O nanoprobe for NIR-II photoacoustic imaging of colon cancer and photothermal-enhanced ferroptosis therapy
2025, Biosensors and Bioelectronics
Imaging guided cancer therapy is a comprehensive strategy that combines the diagnosis and treatment to eradicate tumors. Ferroptosis is a distinct programmed cell death and holds great potential in cancer therapy. In this study, a hydrogen sulfide (H₂S)-activated PEGylated Pd@Cu₂O core-shell nanocomposite (termed PCO) that in situ transformed into Pd@Cu_2-xS (termed PCS) at colorectal tumor tissues is developed for colorectal cancer photoacoustic (PA) imaging and photothermal-enhanced ferroptosis therapy in NIR-II window. The Cu⁺ on the surface of PCS can catalyze the Fenton-like reaction with overexpressed H₂O₂ in the colon tumor tissues, yielding hydroxyl radicals (·OH) and Cu²⁺. Moreover, the PCS accelerates the Fenton-like reaction to generate more ·OH. The PCS displays dual peroxidase- and glutathione oxidase-mimic enzymatic activity in weakly acidic tumor microenvironment (TME). Additionally, the glutathione depletion by Cu²⁺ results in the production of Cu⁺ and glutathione disulfide as well as the down-regulation of glutathione peroxidase 4. The interaction of polyunsaturated fatty acids with ·OH induces the up-regulation of lipid peroxides on cellular membrane, thereby causing ferroptosis. Hence, this study has developed the H₂S-activated PCO that in situ transforms into PCS, as a novel colon cancer diagnosis-treatment nanoprobe, for PA imaging guided precise diagnosis and efficient therapy of colon cancer.

¹: These authors contributed equally.

View Abstract

[1] [1]
Y. Liu, P. Bhattarai, Z. Dai, X. Chen
Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer
Chem. Soc. Rev., 48 (7) (2019), pp. 2053-2108
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Mesoporous platinum@copper selenide-based NIR-II photothermal agents with photothermal conversion efficiency over 80% for photoacoustic imaging and targeted cancer therapy介孔鉑@硒化銅基NIR-II光熱劑，光熱轉換效率超過80%，用於光聲成像和標靶癌症治療