NIR-II Responsive Inorganic 2D Nanomaterials for Cancer Photothermal Therapy: Recent Advances and Future Challenges

Non-invasive cancer photothermal therapy (PTT) is a promising replacement for traditional cancer treatments. The second near-infrared region induced PTT (NIR-II PTT, 1000–1500 nm) with less energy dissipation has been developed for deeper-seated tumor treatment in recent years compared with the traditional first near-infrared light (750–1000 nm). In addition, the use of emerging inorganic 2D nanomaterials as photothermal agents (PTAs) further enhanced PTT efficiency due to their intrinsic photothermal properties. NIR-II light stimulated inorganic 2D nanomaterials for PTT is becoming a hot topic in both academic and clinical fields. This review summarizes the categories, structures, and photothermal conversion properties of inorganic 2D nanomaterials for the first time. The recent synergistic strategies of NIR-II responsive PTT combined with other treatment approaches including chemotherapy, chemodynamic therapy, photodynamic therapy, radiotherapy are summarized. The future challenges and perspectives on these 2D nanomaterials for NIR-II responsive PTT systems construction are further discussed.     

Enlarging the Reservoir: High Absorption Coefficient Dyes Enable Synergetic Near Infrared-II Fluorescence Imaging and Near Infrared-I Photothermal Therapy

Although organic materials with near infrared (NIR)-II fluorescence and a photothermal effect have been widely investigated for the accurate diagnosis and treatment of tumors, optimizing the output signals of both remain challenging. Here, a strategy by “enlarging absorption reservoir” to address this issue, since an increase in photon absorption can naturally enhance output signals, is proposed. As a proof-of-concept, a large π-conjugated diketopyrrolopyrrole (DPP) unit is selected to fabricate strong light-absorbing systems. To enhance solid-state fluorescence, highly twisted alkylthiophene–benzobisthiadiazole–alkylthiophene and triphenylamine rotor are introduced to restrict the strong intermolecular π–π interactions. Moreover, the number of DPP units in molecules is engineered to optimize photophysical properties. Results show that TDADT with two DPP units possesses an exceptionally high molar absorptivity of 2.1 × 10⁵ L mol⁻¹ cm⁻¹ at 808 nm, an acceptable NIR-II quantum yield of 0.1% (emission peak at 1270 nm), and a sizeable photothermal conversion efficiency of 60.4%. The excellent photophysical properties of the TDADT nanoparticles are particularly suitable for in vivo NIR-II imaging-guided cancer surgery and NIR-I photothermal therapy. The presented strategy provides a new approach of designing highly efficient NIR-II phototheranostic agents.     

Renal-Clearable Ultrasmall Polypyrrole Nanoparticles with Size-Regulated Property for Second Near-Infrared Light-Mediated Photothermal Therapy

The critical issue that hinders the translation of nanomaterials from basic research to clinical trials is their potential toxicity caused by long-term body retention. It is still a huge challenge to integrate renal-clearable and theranostic properties into one nanomedicine, especially exploring the nanomaterials with optical absorption in the second near-infrared light (NIR II) biowindow with deep penetration and less tissue scattering. Here, ultrasmall polypyrrole (PPy, ≈2 nm)-based theranostic agents via a facile and green one-step method, which exhibit fluorescence (FL)/photoacoustic (PA)/NIR II multimodal imaging, superior photostability, as well as high photothermal conversion efficiency of 33.35% at 808 nm and 41.97% at 1064 nm is developed. Importantly, these ultrasmall PPy-PEG nanoparticles (NPs) reveal abundant tumor accumulation and efficient renal clearance. Both in vitro and in vivo studies indicate that ultrasmall PPy-PEG NPs have excellent photothermal effect under NIR II laser irradiation that can effectively eliminate the tumors with extremely low systemic toxicity.     

Organic Semiconducting Macromolecular Dyes for NIR-II Photoacoustic Imaging and Photothermal Therapy

Owing to the unique advantages of photoacoustic imaging (PAI) and photothermal therapy (PTT) conducted over the near-infrared-II (NIR-II) window, the development of high-efficiency optical agents with NIR-II light responsiveness is of great significance. Despite the diversity of optical agents developed for NIR-II PAI and PTT, most of them are based on inorganic nanomaterials and small molecular dyes, whose biosafety and photostability need to be further assessed, respectively. Organic semiconducting macromolecular dyes (OSMDs) featuring a large semiconducting backbone are becoming alternative candidates for NIR-II PAI and PTT owing to their reliable biocompatibility, durable photostability, and ideal photothermal conversion capability. This paper reviews the current progress of OSMD-based PAI and PTT in the NIR-II optical window. The three main types of OSMDs with different skeleton architectures are introduced, and their applications for NIR-II PAI (tumor imaging, stem cell tracking, and vasculature imaging) and PTT (tumor ablation) are described. Viable strategies for further improving the NIR-II PAI performance of OSMDs are discussed. Finally, some major issues faced by OSMDs in NIR-II PAI and PTT are raised, and the future development directions of OSMDs are analyzed.     

A NIR-II AIEgen-Based Supramolecular Nanodot for Peroxynitrite-Potentiated Mild-Temperature Photothermal Therapy of Hepatocellular Carcinoma

Compared to conventional photothermal therapy (PTT) which requires hyperthermia higher than 50 °C, mild-temperature PTT is a more promising antitumor strategy with much lower phototoxicity to neighboring normal tissues. However, the therapeutic efficacy of mild-temperature PTT is always restricted by the thermoresistance of cancer cells. To address this issue, a supramolecular drug nanocarrier is fabricated to co-deliver nitric oxide (NO) and photothermal agent DCTBT with NIR-II aggregation-induced emission (AIE) characteristic for mild-temperature PTT. NO can be effectively released from the nanocarriers in intracellular reductive environment and DCTBT is capable of simultaneously producing reactive oxygen species (ROS) and hyperthermia upon 808 nm laser irradiation. The generated ROS can further react with NO to produce peroxynitrite (ONOOˉ) bearing strong oxidization and nitration capability. ONOOˉ can inhibit the expression of heat shock proteins (HSP) to reduce the thermoresistance of cancer cells, which is necessary to achieve excellent therapeutic efficacy of DCTBT-based PTT at mild temperature (<50 °C). The antitumor performance of ONOOˉ-potentiated mild-temperature PTT is validated on subcutaneous and orthotopic hepatocellular carcinoma (HCC) models. This research puts forward an innovative strategy to overcome thermoresistance for mild-temperature PTT, which provides new inspirations to explore ONOOˉ-sensitized tumor therapy strategies.     

In Situ Nanozyme-Amplified NIR-II Phototheranostics for Tumor-Specific Imaging and Therapy

The discovery of near-IR-II (NIR-II) tumor phototheranostics holds a great promise for use in nanomedicine on account of its enhanced penetration depth, high spatial resolution, and noninvasiveness. However, contemporary “always on” phototherapeutic agents often have many undesirable side effects that hinder their clinical trial progress. To overcome this dilemma, an in situ nanozyme-amplified chromogenic nanoreactor by loading 3,3′,5,5′-tetramethylbenzidine (TMB) and ultrasmall PtAu nanoparticles into a metal–organic framework is developed for specific tumor theranostics, leaving normal tissues unharmed. As an intelligent photoacoustic diagnostic agent, the as-constructed nanoreactor remains silent until they enter the tumor site (H₂O₂-activated and acid-enhanced conditions) and turns on the photoacoustic signal to render a preoperative tumor diagnosis. As a nanozyme, the special microenvironment of the tumor tissue is used to initiate its catalytic damage by reactive oxygen species for chemodynamic therapy (CDT). More importantly, the TMB is oxidized, and the subsequent photothermal therapy (PTT) can be realized, leading to an optimal combination of CDT and PTT to concurrently fight obstinate cancers. The present “all-in-one” phototheranostics utilize nanozyme-augmented NIR-II agents for specific tumor ablation, which are promising for further development of intelligent nanozymes in tumor therapy.     

Rational Design of Near-infrared II Plasmonic Optofunctional Materials for Diagnostic and Therapeutic Applications

Plasmonic materials have aroused considerable interest in diagnostic and therapeutic biomedical applications because of their remarkable optical properties and the integration of multiple functionalities. Particularly, near-infrared II (NIR-II) plasmonic materials present great advantages for anticancer treatments, including deep tissue penetration, low tissue light scattering and autofluorescence, and high spatial resolution. Thus, NIR-II plasmonic phototheranostics represents a promising approach for effective anticancer treatments through multi-modal imaging-guided therapy. Accordingly, tremendous efforts have recently been devoted to the development of NIR-II plasmonic materials for highly efficient phototheranostics. In this review, the recent progress of NIR-II plasmonic materials and their phototheranostic applications are overviewed. First, the localized surface plasmon resonance effect and the related optical properties such as the photothermal effect, photoacoustic effect, and surface-enhanced Raman scattering (SERS) effect are introduced. Then, the unique features and the structure-property relationship of various types of NIR-II plasmonic materials are discussed. Finally, the recent progress of NIR-II plasmonic material-based multimodal phototheranostics with an emphasis on the integration of multiple functionalities are reviewed, and subsequently the current challenges and future research perspectives are discussed. This review will provide valuable guidelines for the rational design of NIR-II plasmonic materials for highly efficient cancer phototheranostics in the future.     

Ultrasmall Semiconducting Polymer Dots with Rapid Clearance for Second Near‐Infrared Photoacoustic Imaging and Photothermal Cancer Therapy

Phototheranostic agents in the second near‐infrared (NIR‐II) window (1000–1700 nm) are emerging as a promising theranostic platform for precision medicine due to enhanced penetration depth and minimized tissue exposure. The development of metabolizable NIR‐II nanoagents for imaging‐guided therapy are essential for noninvasive disease diagnosis and precise ablation of tumors. Herein, metabolizable highly absorbing NIR‐II conjugated polymer dots (Pdots) are reported for the first time for photoacoustic imaging guided photothermal therapy (PTT). The unique design of low‐bandgap D‐A π‐conjugated polymer (DPP‐BTzTD) together with modified nanoreprecipitation conditions allows to fabricate NIR‐II absorbing Pdots with ultrasmall (4 nm) particle size. Extensive experimental tests demonstrate that the constructed Pdots exhibit good biocompatibility, excellent photostability, bright photoacoustic signals, and high photothermal conversion efficiency (53%). In addition, upon tail‐vein intravenous injection of tumor‐bearing mice, Pdots also show high‐efficient tumor ablation capability with rapid excretion from the body. In particular, both in vitro and in vivo assays indicate that the Pdots possess remarkable PTT performance under irradiation with a 1064 nm laser with 0.5 W cm^?2, which is much lower than its maximum permissible exposure limit of 1 W cm^?2. This pilot study thus paves a novel avenue for the development of organic semiconducting nanoagents for future clinical translation.     

NIR-II J-Aggregates Labelled Mesoporous Implant for Imaging-Guided Osteosynthesis with Minimal Invasion

Medical implants are widely used in clinical practice, such as cardiovascular stenting, maxillofacial surgery, and orthopedics. However, most of the traditional implant operations are open and invasive, resulting in massive dissection of soft tissue and interruption of blood supply. The accurate navigation for the implant operations is considered as one of the most effective ways to reduce the damage, which is urgently desired in clinic. Herein, a biocompatible NIR-II J-aggregates labelled mesoporous implant for imaging-guided osteosynthesis with minimal invasion is reported. Mesoporous silica layer with vertical channels is grown on the surface of titanium plate, which can provide the confining space for the formation of the FD-1080 J-aggregates. Both the absorption and fluorescence peaks of the FD-1080 J-aggregates are located in NIR-II window (beyond 1300 nm), which are ideal for high resolution and real time surgical navigation in deep tissue. NIR-II imaging can clearly display the location and outline of the implant both in vitro and in vivo. This NIR-II imaging-guided osteosynthesis can effectively reduce the surgical wound and operational duration, which is crucial for the implant surgeries.     

Zwitterionic AIEgens: Rational Molecular Design for NIR-II Fluorescence Imaging-Guided Synergistic Phototherapy

Fluorescence imaging in the second near-infrared region (NIR-II) can penetrate tissue at centimeter depths and obtain high image fidelity. However, facile synthesis of small-molecule fluorescent photosensitizers for efficient NIR-II fluorescence imaging as well as photodynamic and photothermal combinatorial therapies is still a challenging task. Herein, a rational design and facile synthesis protocol are reported for a series of novel NIR-emissive zwitterionic luminogens with aggregation-induced emission (AIE) features for cancer phototheranostics. Consistent with the intrinsic features including long emission wavelength, effective reactive oxygen species generation, and excellent photothermal conversion efficiency (35.76%), in vitro and in vivo evaluation show that one of these presented AIE luminogens provides excellent performance in NIR-II fluorescence imaging-guided synergistic phototherapy against cancer.     

Rattle‐Type Fe3O4@CuS Developed to Conduct Magnetically Guided Photoinduced Hyperthermia at First and Second NIR Biological Windows

A therapeutic carrier in the second near‐infrared (NIR) window is created that features magnetic target, magnetic resonance imaging (MRI) diagnosis, and photothermal therapy functions through the manipulation of a magnet and NIR laser. A covellite‐based CuS in the form of rattle‐type Fe₃O₄@CuS nanoparticles is developed to conduct photoinduced hyperthermia at 808 and 1064 nm of the first and second NIR windows, respectively. The Fe₃O₄@CuS nanoparticles exhibit broad NIR absorption from 700 to 1300 nm. The in vitro photothermal results show that the laser intensity obtained using 808 nm irradiation required a twofold increase in its magnitude to achieve the same damage in cells as that obtained using 1064 nm irradiation. Because of the favorable magnetic property of Fe₃O₄, magnetically guided photothermal tumor ablation is performed for assessing both laser exposures. According to the results under the fixed laser intensity and irradiation spot, exposure to 1064 nm completely removed tumors showing no signs of relapse. On the other hand, 808 nm irradiation leads to effective inhibition of growth that remained nearly unchanged for up to 30 d, but the tumors are not completely eliminated. In addition, MRI is performed to monitor rattle‐type Fe₃O₄@CuS localization in the tumor following magnetic attraction.     

Anionic Solid Solution MXene for Low-Dosage NIR-II Tumor Photothermal Therapy

Due to the deep biological penetrability and therapeutic depth, the photothermal therapy over second near-infrared region (NIR-II) is booming against deep-seated tumors. Intensive endeavors are committed to looking for suitable photothermal agents (PTAs), but the progress seems not so satisfied toward the choice of PTA dosage. Herein, a comprehensive parameter, incident photon-to-thermal conversion coefficient (IPTCE), is used to evaluate the overall conversion of PTAs at different dosage, which will benefit for determining the optimized dosage of PTAs in pursuit of complete healing together with reduced long-term damages of nanodrugs. To prove the possibility, a series of anionic solid solution MXenes are chosen as hosts due to their versatile chemical compositions and correspondingly tunable light response. By deconvoluting fundamental structure–composition–property relationships, anionic regulation with extra electron injection leads to tunable free carrier densities and enhanced NIR-II harvesting. Ti₃C_1.23N_0.77 with high-level nitrogen exhibits extraordinary extinction coefficient (43.5 L g⁻¹ cm⁻¹) than other MXenes. The parameter of IPTCE can guide the choice of PTA concentration for complete photothermal healing in vitro and vivo. This proof-of-principle demonstration highlights synthetically tailoring of the light harvesting over NIR-II biowindow for a given host material by anionic regulation and further optimizes tumor photothermal therapy at low dose.     

An Acceptor–Donor–Acceptor Structured Small Molecule for Effective NIR Triggered Dual Phototherapy of Cancer

Dual phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is regarded as a more effective method for cancer treatment than single PDT or PTT. However, development of single component and near‐infrared (NIR) triggered agents for efficient dual phototherapy remains a challenge. Herein, a simple strategy to develop dual‐functional small‐molecules‐based photosensitizers for combined PDT and PTT treatment is proposed through: 1) finely modulating HOMO–LUMO energy levels to regulate the intersystem crossing (ISC) process for effective singlet oxygen (¹O₂) generation for PDT; 2) effectively inhibiting fluorescence via strong intramolecular charge transfer (ICT) to maximize the conversion of photo energy to heat for PTT or ISC process for PDT. An acceptor–donor–acceptor (A‐D‐A) structured small molecule (CPDT) is designed and synthesized. The biocompatible nanoparticles, FA‐CNPs, prepared by encapsulating CPDT directly with a folate functionalized amphipathic copolymer, present strong NIR absorption, robust photostability, cancer cell targeting, high photothermal conversion efficiency as well as efficient ¹O₂ generation under single 808 nm laser irradiation. Furthermore, synergistic PDT and PTT effects of FA‐CNPs in vivo are demonstrated by significant inhibition of tumor growth. The proposed strategy may provide a new approach to reasonably design and develop safe and efficient photosensitizers for dual phototherapy against cancer.     

PEGylated Micelle Nanoparticles Encapsulating a Non‐Fluorescent Near‐Infrared Organic Dye as a Safe and Highly‐Effective Photothermal Agent for In Vivo Cancer Therapy

Photothermal therapy (PTT), as a minimally invasive and highly effective cancer treatment approach, has received widespread attention in recent years. Tremendous effort has been devoted to explore various types of photothermal agents with high near‐infrared (NIR) absorbance for PTT cancer treatment. Despite many exciting progresses in the area, effective yet safe photothermal agents with good biocompatibility and biodegradability are still highly desired. In this work, a new organic PTT agent based on polyethylene glycol (PEG) coated micelle nanoparticles encapsulating a heptamethine indocyanine dye IR825 is developed, showing a strong NIR absorption band and a rather low quantum yield, for in vivo photothermal treatment of cancer. It is found that the IR825–PEG nanoparticles show ultra‐high in vivo tumor uptake after intravenous injection, and appear to be an excellent PTT agent for tumor ablation under a low‐power laser irradiation, without rendering any appreciable toxicity to the treated animals. Compared with inorganic nanomaterials and conjugated polymers being explored in PTT, the NIR‐absorbing micelle nanoparticles presented here may have the least safety concern while showing excellent treatment efficacy, and thus may be a new photothermal agent potentially useful in clinical applications.     

Molecular Engineering of Near-Infrared-II Photosensitizers with Steric-Hindrance Effect for Image-Guided Cancer Photodynamic Therapy

The design of photosensitizers (PSs) with fluorescence in the second near-infrared (NIR-II, 1000–1700 nm) window remains a challenge, as the introduction of donor or acceptor units with excessively strong electron-withdrawing or donating ability leads to longer-wavelength emission but insufficient production of singlet oxygen (¹O₂). In this study, a series of acceptor-donor-acceptor-donor-acceptor-type PSs are designed by adjusting the steric hindrance of the molecules. Compound BNET forms a dihedral angle of 88° with a nearly vertically twisted backbone to show that the intensity of local emission in the first near-infrared (750–900 nm) region declines in the aggregated state, while the emission peaks of twisted intramolecular charge transfer span over 1000 nm with significant enhancement. The albumin-bound NIR-II PS nanoparticles exhibit efficient ¹O₂ generation, good photostability and biocompatibility, and negligible dark toxicity. The nanoparticles demonstrate high specific NIR-II fluorescence imaging of tumor lesions as well as effective image-guided photodynamic therapy in mice bearing orthotopic colon cancer or pancreatic cancer. The designed NIR-II PS nanoparticles show great potential for biomedical applications.     

Enhanced Antitumor Efficacy by 808 nm Laser‐Induced Synergistic Photothermal and Photodynamic Therapy Based on a Indocyanine‐Green‐Attached W18O49 Nanostructure

A novel nanoplatform based on tungsten oxide (W₁₈O₄₉, WO) and indocyanine green (ICG) for dual‐modal photothermal therapy (PTT) and photodynamic therapy (PDT) has been successfully constructed. In this design, the hierarchical unique nanorod‐bundled W₁₈O₄₉ nanostructures play roles in being not only as an efficient photothermal agent for PTT but also as a potential nanovehicle for ICG molecules via electrostatic adsorption after modified with trimethylammonium groups on their surface. It is found that the ability of ICG to produce cytotoxic reactive oxygen species for PDT is well maintained after being attached on the WO, thus the as‐obtained WO@ICG can achieve a synergistic effect of combined PTT and PDT under single 808 nm near‐infrared (NIR) laser excitation. Notably, compared with PTT or PDT alone, the enhanced HeLa cells lethality of the 808 nm laser triggered dual‐modal therapy is observed. The in vivo animal experiments have shown that WO@ICG has effective solid tumor ablation effect with 808 nm NIR light irradiation, revealing the potential of these nanocomposites as a NIR‐mediated dual‐modal therapeutic platform for cancer treatment.     

Recent Advances and Clinical Potential of Near Infrared Photothermal Conversion Materials for Photothermal Hepatocellular Carcinoma Therapy

Growing concern about photothermal tumor therapy (PTT) as a promising alternative to conventional liver cancer treatment, which is a treatment strategy that utilizes near-infrared (NIR) light-induced photothermal agents (PTAs) to yield photothermal effects to localize thermal damage for tumors. Herein, given the gap between experimental research and clinical application, this review seeks to timely summarize and highlight the recent progress of PTAs used for photothermal treatment of liver cancer in vivo and in vitro in the last five-year. The implications of various PTAs on the multifunctional photothermal conversion capability, the structure-performance correlations of PTT, together with the evaluation of their potential in application are systematically dissected to further dig out what the buried mechanism is. Besides, higher requirements are put forward for the discrepancies and crucial issues faced by different PTAs in PTT with related medical technical obstacles being conquered, which lays a solid theoretical foundation for the medical field of oncology treatment as a whole, especially liver cancer. Finally, it is expected that this review can present valuable guidance for the design of efficient, photostability, and biosafety-aware PTAs for anticancer therapy while stepping into the fast traffic lane for the conversion from bench to bedside in the foreseeable future.     

Tumor‐Penetrating Nanotherapeutics Loading a Near‐Infrared Probe Inhibit Growth and Metastasis of Breast Cancer

The tumor growth and metastasis is the leading reason for the high mortality of breast cancer. Herein, it is first reported a deep tumor‐penetrating photothermal nanotherapeutics loading a near‐infrared (NIR) probe for potential photothermal therapy (PTT) of tumor growth and metastasis of breast cancer. The NIR probe of 1,1‐dioctadecyl‐3,3,3,3‐tetramethylindotricarbocyanine iodide (DiR), a lipophilicfluorescent carbocyanine dye with strong light‐absorbing capability, is entrapped into the photothermal nanotherapeutics for PTT application. The DiR‐loaded photothermal nanotherapeutics (DPN) is homogeneous nanometer‐sized particles with the mean diameter of 24.5 ± 4.1 nm. Upon 808 nm laser irradiation, DPN presents superior production of thermal energy than free DiR both in vitro and in vivo. The cell proliferation and migration activities of metastatic 4T1 breast cancer cells are obviously inhibited by DPN in combination with NIR irradiation. Moreover, DPN can induce a higher accumulation in tumor and penetrate into the deep interior of tumor tissues. The in vivo PTT measurements indicate that the growth and metastasis of breast cancer are entirely inhibited by a single treatment of DPN with NIR irradiation. Therefore, the deep tumor‐penetrating DPN can provide a promising strategy for PTT of tumor progression and metastasis of breast cancer.