Renal-Clearable Nickel-Doped Carbon Dots with Boosted Photothermal Conversion Efficiency for Multimodal Imaging-Guided Cancer Therapy in the Second Near-Infrared Biowindow

Photothermal agents with absorption in the second near-infrared (NIR-II) biowindow have attracted increasing attention for photothermal therapy (PTT) on account of their deeper tissue penetration capacity. However, most of the current NIR-II photothermal agents exhibit low photothermal conversion efficiency (PCE) and long-term biotoxicity. To overcome these shortcomings, herein, nickel and nitrogen co-doped carbon dots (Ni-CDs, ≈4.6 nm) are prepared via a facile one-pot hydrothermal approach for imaging-guided PTT in the NIR-II window. The Ni-CDs exhibit significant absorption in the NIR-II region with a distinguished PCE as high as 76.1% (1064 nm) and have excellent photostability and biocompatibility. Furthermore, the Ni-CDs can be employed as photothermal, photoacoustic, and magnetic resonance imaging contrast agents because of their outstanding photothermal effect and instinctive paramagnetic feature. The Ni-CDs demonstrate significant PTT efficacy of tumor upon 1064 nm irradiation with a low power density (0.5 W cm⁻²). The Ni-CDs can be eliminated from the body via a renal filtration pathway, thereby minimizing their long-term biotoxicity. Therefore, this work provides a simple and feasible approach to develop photothermal agents with remarkable PCE in the NIR-II region, presenting good biosafety for multimodal imaging-guided PTT of tumor.     

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.     

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.     

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.     

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.     

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.     

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.     

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.     

Significant Enhancement of Photothermal and Photoacoustic Efficiencies for Semiconducting Polymer Nanoparticles through Simply Molecular Engineering

Semiconducting polymer nanoparticles (SP NPs) are employed as efficient nanoagents for “all‐in‐one” theranostic nanoplatforms with dual photoacoustic imaging (PAI) and photothermal therapy (PTT) functions based on their photothermal conversion effect. However, the mechanisms of tuning the PTT efficiency are still elusive, though several SP NPs with high photothermal efficiency are reported. Herein, two donor–acceptor (D–A) SP NPs PTIGSVS and PIIGSVS with the same donor unit but different acceptor units are designed and synthesized. Through tuning the acceptor unit, PTIGSVS shows more planar backbone structure, stronger D–A strength, redshifted absorption, enhanced extinction efficient, weakened emission properties, and more efficient nonradiative decay in comparison to the polymeric analogue PIIGSVS . Thus, PTIGSVS NPs present much higher photothermal conversion efficiencies (74%) than PIIGSVS NPs (11%), resulting in significantly enhanced in vitro and in vivo PAI and PTT performance. This contribution demonstrates that PTIGSVS NPs are superior PA/PTT agents for effective cancer theranostic and shed light on understanding the relationship between molecular structures and photothermal effect of CPs.     

Designing Bioinspired 2D MoSe2 Nanosheet for Efficient Photothermal‐Triggered Cancer Immunotherapy with Reprogramming Tumor‐Associated Macrophages

Nonspecific absorption and clearance of nanomaterials during circulation is the major cause for treatment failure in nanomedicine‐based cancer therapy. Therefore, herein bioinspired red blood cell (RBC) membrane is employed to camouflage 2D MoSe₂ nanosheets with high photothermal conversion efficiency to achieve enhanced hemocompatibility and circulation time by preventing macrophage phagocytosis. RBC–MoSe₂‐potentiated photothermal therapy (PTT) demonstrates potent in vivo antitumor efficacy, which triggers the release of tumor‐associated antigens to activate cytotoxic T lymphocytes and inactivate the PD‐1/PD‐L1 pathway to avoid immunologic escape. Furthermore, in the ablated tumor microenvironment, the tumor‐associated macrophages are effectively reprogrammed to tumoricidal M1 phenotype to potentiate the antitumor action. Taken together, this biomimetic functionalization thus provides a substantial advance in personalized PTT‐triggered immunotherapy for clinical translation.     

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.     

pH‐Responsive Cyanine‐Grafted Graphene Oxide for Fluorescence Resonance Energy Transfer‐Enhanced Photothermal Therapy

Stimuli‐responsive anticancer agents are of particular interest in the field of cancer therapy. Nevertheless, so far stimuli‐responsive photothermal agents have been explored with limited success for cancer photothermal therapy (PTT). In this work, as a proof‐of‐concept, a pH‐responsive photothermal nanoconjugate for enhanced PTT efficacy, in which graphene oxide (GO) with broad NIR absorbance and effective photothermal conversion efficiency is selected as a typical model receptor of fluorescence resonance energy transfer (FRET), and grafted cyanine dye (e.g., Cypate) acts as the donor of near‐infrared fluorescence (NIRF), is reported for the first time. The conjugate of Cypate‐grafted GO exhibits different conformations in aqueous solutions at various pH, which can trigger pH‐dependent FRET effect between GO and Cypate and thus induce pH‐responsive photothermal effect of GO‐Cypate. GO‐Cypate exhibits severe cell damage owing to the enhanced photothermal effect in lysosomes, and thus generate synergistic PTT efficacy with tumor ablation upon photoirradiation after a single‐dose intravenous injection. The photothermal nanoconjugate with broad NIR absorbance as the effective receptor of FRET can smartly convert emitted NIRF energy from donor cyanine dye into additional photothermal effect for improving PTT. These results suggest that the smart nanoconjugate can act as a promising stimuli‐responsive photothermal nanoplatform for cancer therapy.     

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.     

Multifunctional Carbon–Silica Nanocapsules with Gold Core for Synergistic Photothermal and Chemo‐Cancer Therapy under the Guidance of Bimodal Imaging

Carbon‐based nanomaterials have been developed for photothermal cancer therapy, but it is still a great challenge to fabricate their multifunctional counterparts with facile methods, good biocompatibility and dispersity, and high efficiency for cancer theranostics. In this work, an alternative multifunctional nanoplatform is developed based on carbon–silica nanocapsules with gold nanoparticle in the cavity (Au@CSN) for cancer theranostics. The encapsulated chemodrug doxorubicin can be released from the Au@CSN with mesoporous and hollow structure in a near‐infrared light and pH stimuli‐responsive manner, facilitating spatiotemporal therapy to decrease off‐target toxicity. The nanocapsules with efficient photothermal conversion and excellent biocompatibility achieve a synergistic effect of photothermal and chemotherapy. Furthermore, the nanocapsules can act as a multimodal imaging agent of computed tomography and photoacoustic tomography imaging for guiding the therapy. This new design platform can provide a promising strategy for precise cancer theranostics.     

Nanoheterojunction Engineering Enables NIR-II-Triggered Photonic Hyperthermia and Pyroelectric Catalysis for Tumor-Synergistic Therapy

Photodynamic therapy (PDT) as a non-invasive strategy shows high promise in cancer treatment. However, owing to the hypoxic tumor microenvironment and light irradiation-mediated rapid electron–hole pair recombination, the therapeutic efficacy of PDT is dramatically discounted by limited reactive oxygen species (ROS) generation. Herein, a multifunctional theranostic nanoheterojunction is rationally developed, in which 2D niobium carbide (Nb₂C) MXene is in situ grown with barium titanate (BTO) to generate a robust photo-pyroelectric catalyst, termed as BTO@Nb₂C nanosheets, for enhanced ROS production, originating from the effective electron–hole pair separation induced by the pyroelectric effect. Under the second near-infrared (NIR-II) laser irradiation, Nb₂C MXene core-mediated photonic hyperthermia regulates temperature variation around BTO shells facilitating the electron–hole spatial separation, which reacts with the surrounding O₂ and H₂O molecules to yield toxic ROS, achieving a synergetic effect by means of combinaterial photothermal therapy with pyrocatalytic therapy. Correspondingly, the engineered BTO@Nb₂C composite nanosheets feature benign biocompatibility and high antitumor efficiency with the tumor-inhibition rate of 94.9% in vivo, which can be applied as an imaging-guided real-time non-invasive synergetic dual-mode therapeutic nanomedicine for efficient tumor nanotherapy.