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.     

PEGylated Polypyrrole Nanoparticles Conjugating Gadolinium Chelates for Dual‐Modal MRI/Photoacoustic Imaging Guided Photothermal Therapy of Cancer

Polypyrrole nanoparticles conjugating gadolinium chelates were successfully fabricated for dual‐modal magnetic resonance imaging (MRI) and photoacoustic imaging guided photothermal therapy of cancer, from a mixture of pyrrole and pyrrole‐1‐propanoic acid through a facile one‐step aqueous dispersion polymerization, followed by covalent attachment of gadolinium chelate, using polyethylene glycol as a linker. The obtained PEGylated poly­pyrrole nanoparticles conjugating gadolinium chelates (Gd‐PEG‐PPy NPs), sized around around 70 nm, exhibited a high T₁ relaxivity coefficient of 10.61 L mm ^?1 s^?1, more than twice as high as that of the relating free Gd³⁺ complex (4.2 L mm ^–1 s^?1). After 24 h intravenous injection of Gd‐PEG‐PPy NPs, the tumor sites exhibited obvious enhancement in both T₁‐weighted MRI intensity and photoacoustic signal compared with that before injection, indicating the efficient accumulation of Gd‐PEG‐PPy NPs due to the introduction of the PEG layer onto the particle surface. In addition, tumor growth could be effectively inhibited after treatment with Gd‐PEG‐PPy NPs in combination with near‐infrared laser irradiation. The passive targeting and high MRI/photo­acoustic contrast capability of Gd‐PEG‐PPy NPs are quite favorable for precise cancer diagnosing and locating the tumor site to guide the external laser irradiation for photothermal ablation of tumors without damaging the surrounding healthy tissues. Therefore, Gd‐PEG‐PPy NPs may assist in better monitoring the therapeutic process, and contribute to developing more effective “personalized medicine,” showing great potential for cancer diagnosis and therapy.     

Ultra‐Small Iron Oxide Doped Polypyrrole Nanoparticles for In Vivo Multimodal Imaging Guided Photothermal Therapy

Recently, near‐infrared (NIR) absorbing conjugated polymeric nanoparticles have received significant attention in photothermal therapy of cancer. Herein, polypyrrole (PPy), a NIR‐absorbing conjugate polymer, is used to coat ultra‐small iron oxide nanoparticles (IONPs), obtaining multifunctional IONP@PPy nanocomposite which is further modified by the biocompatible polyethylene glycol (PEG) through a layer‐by‐layer method to acquire high stability in physiological solutions. Utilizing the optical and magnetic properties of the yielded IONP@PPy‐PEG nanoparticles, in vivo magnetic resonance (MR) and photoacoustic imaging of tumor‐bearing mice are conducted, revealing strong tumor uptake of those nanoparticles after intravenous injection. In vivo photothermal therapy is then designed and carried out, achieving excellent tumor ablation therapeutic effect in mice experiments. These results promise the use of multifunctional NIR‐absorbing organic‐inorganic hybrid nanomaterials, such as IONP@PPy‐PEG presented here, for potential applications in cancer theranostics.     

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.     

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.     

Protease-Activatable Nanozyme with Photoacoustic and Tumor-Enhanced Magnetic Resonance Imaging for Photothermal Ferroptosis Cancer Therapy

Despite the promise of ferrotherapy in cancer treatment, current ferrous therapeutics suffer from compromised antitumor ferroptosis efficacy and low specificity for tumors. Herein, a protease-activatable nanozyme (Fe₃O₄@Cu_1.77Se) is reported for photoacoustic and tumor-enhanced magnetic resonance imaging (MRI)-guided second near-IR photothermal ferroptosis cancer therapy. Fe₃O₄@Cu_1.77Se remains stable in physiological conditions, but disintegrates to increase reactive intratumoral ferrous supply for elevated hydroxyl radical generation by Fenton reaction and GSH depletion in response to overexpressed matrix metalloproteinases in tumor microenvironment, leading to amplified ferroptosis of tumor cells as well as enhanced T₂-weighted MRI contrast. Further integration with second near-IR photoirradiation to generate localized heat not only triggers effective photothermal therapy and photoacoustic imaging but more importantly, potentiates Fenton reaction to promote ferroptotic tumor cell death. Such synergism leads to the polarization of tumor-associated macrophage from the tumor-promoting M2 type to the tumor-killing M1 type, and induces the immunogenic cells death of tumor cells, which in turn promotes the maturation of dendritic cells and infiltration of cytotoxic T lymphocytes in tumor, contributing to significant tumor suppression. This study presents a novel activatable ferrous nanotheranostics for spatial-temporal control over antitumor ferroptosis responses.     

Effective Eradication of Tumors by Enhancing Photoacoustic-Imaging-Guided Combined Photothermal Therapy and Ultrasonic Therapy

Exploiting a comprehensive strategy that processes diagnosis and therapeutic functions is desired for eradicating tumors. In this study, two versatile nanoparticles are introduced: one is polyethylene glycol- and polyethyleneimine-modified gold nanorods (mPEG–PEI–AuNRs), and the other is formed by electrostatic interactions between mPEG–PEI and calcium carbonate nanoparticles (mPEG–PEI/CaNPs). These two nanoparticles possess following favorable properties: 1) mPEG–PEI–AuNRs and mPEG–PEI/CaNPs show not only high cell uptake in acidic tumoral pH, but also efficient accumulation in tumors with prolonged circulation. 2) mPEG–PEI/CaNPs can generate carbon dioxide (CO₂) bubbles in acidic tumoral environment and the photoacoustic (PA) signals from mPEG–PEI–AuNRs can be enhanced with the generation of CO₂ bubbles. 3) The tumors can be eradicated by combining photothermal therapy (PTT) with ultrasonic therapy (UST) under the near-infrared (NIR) laser and ultrasonic irradiation with the presence of mPEG–PEI–AuNRs and CO₂ bubbles from mPEG–PEI/CaNPs. The detailed evaluation of cellular uptake, photothermal property of mPEG–PEI–AuNRs, CO₂ bubbles’ generation from mPEG–PEI/CaNPs, imaging, and combined PTT and UST are carried out in vitro or in vivo. This work has great potential usage for diagnosis and treatment in the future.     

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.     

Intracellular Bottom-up Synthesis of Ultrasmall CuS Nanodots in Cancer Cells for Simultaneous Photothermal Therapy and COX-2 Inactivation

The clinical application of photothermal therapy (PTT) is limited by the accuracy of thermal damage and the risk of tumor metastasis and relapse induced by hyperthermia-related inflammation. Intracellular bottom-up synthesis (iBuS) of CuS nanoparticles from small-molecule precursors inside tumor cells triggered by tumor specific stimuli is a promising strategy to enhance the precision of PTT treatment and reduce the risk of nondegradable metal nanoparticles. Herein, monolocking nanoparticles (MLNPs) with Cu-meloxicam complexes encapsulated by human serum albumin (HSA) are reported, which efficiently form CuS nanodots via the elevated concentration of endogenous H₂S inside tumor cells and meanwhile release meloxicam for anti-inflammatory effects. The intracellular bottom-up fabrication of CuS nanodots is directly visualized by TEM. An enhanced PTT effect is observed with 4T1 cells caused by additional meloxicam-induced inactivation of the COX-2 enzyme. After systemic administration, MLNPs completely ablate tumors under laser exposure, simultaneously inhibiting the inflammation induced by photothermal damage, and can be cleared via the kidney into urine. This strategy provides a new route for activated multimodal therapy, which could be applicable to precisely combat cancer.     

Assembly of Au Plasmonic Photothermal Agent and Iron Oxide Nanoparticles on Ultrathin Black Phosphorus for Targeted Photothermal and Photodynamic Cancer Therapy

Photodynamic therapy (PDT), as a minimally invasive and high‐efficiency anticancer approach, has received extensive research attention recently. Despite plenty of effort devoted to exploring various types of photodynamic agents with strong near‐infrared (NIR) absorbance for PDT and many encouraging progresses achieved in the area, effective and safe photodynamic photosensitizers with good biodegradability and biocompatibility are still highly expected. In this work, a novel nanocomposite has been developed by assembly of iron oxide (Fe₃O₄) nanoparticles (NPs) and Au nanoparticles on black phosphorus sheets (BPs@Au@Fe₃O₄), which shows a broad light absorption band and a photodegradable character. In vitro and in vivo assay indicates that BPs@Au@Fe₃O₄ nanoparticles are highly biocompatible and exhibit excellent tumor inhibition efficacy owing to a synergistic photothermal and photodynamic therapy mediated by a low‐power NIR laser. Importantly, BPs@Au@Fe₃O₄ can anticipatorily suppress tumor growth by visualized synergistic therapy with the help of magnetic resonance imaging (MRI). This work presents the first combination application of the photodynamic and photothermal effect deriving from black phosphorus nanosheets and plasmonic photothermal effect from Au nanoparticles together with MRI from Fe₃O₄ NPs, which may open the new utilization of black phosphorus nanosheets in biomedicine, optoelectronic devices, and photocatalysis.     

Ultrasmall CuCo2S4 Nanocrystals: All‐in‐One Theragnosis Nanoplatform with Magnetic Resonance/Near‐Infrared Imaging for Efficiently Photothermal Therapy of Tumors

Copper‐based ternary bimetal chalcogenides have very promising potential as multifunctional theragnosis nanoplatform for photothermal treatment of tumors. However, the design and synthesis of such an effective platform remains challenging. In this study, hydrophilic CuCo₂S₄ nanocrystals (NCs) with a desirable size of ≈10 nm are synthesized by a simple one‐pot hydrothermal route. The as‐prepared ultrasmall CuCo₂S₄ NCs show: 1) intense near‐infrared absorption, which is attributed to 3d electronic transitions from the valence band to an intermediate band, as identified by density functional theory calculations; 2) high photothermal performance with a photothermal conversion efficiency up to 73.4%; and 3) capability for magnetic resonance (MR) imaging, as a result of the unpaired 3d electrons of cobalt. Finally, it is demonstrated that the CuCo₂S₄ NCs are a promising “all‐in‐one” photothermal theragnosis nanoplatform for photothermal cancer therapy under the irradiation of a 915 nm laser at a safe power density of 0.5 W cm^?2, guided by MR and infrared thermal imaging. This work further promotes the potential applications of ternary bimetal chalcogenides for photothermal theragnosis therapy.     

Biocompatible D–A Semiconducting Polymer Nanoparticle with Light‐Harvesting Unit for Highly Effective Photoacoustic Imaging Guided Photothermal Therapy

The development of nanotheranostic agents that integrate diagnosis and therapy for effective personalized precision medicine has obtained tremendous attention in the past few decades. In this report, biocompatible electron donor–acceptor conjugated semiconducting polymer nanoparticles (PPor‐PEG NPs) with light‐harvesting unit is prepared and developed for highly effective photoacoustic imaging guided photothermal therapy. To the best of our knowledge, it is the first time that the concept of light‐harvesting unit is exploited for enhancing the photoacoustic signal and photothermal energy conversion in polymer‐based theranostic agent. Combined with additional merits including donor–acceptor pair to favor electron transfer and fluorescence quenching effect after NP formation, the photothermal conversion efficiency of the PPor‐PEG NPs is determined to be 62.3%, which is the highest value among reported polymer NPs. Moreover, the as‐prepared PPor‐PEG NP not only exhibits a remarkable cell‐killing ability but also achieves 100% tumor elimination, demonstrating its excellent photothermal therapeutic efficacy. Finally, the as‐prepared water‐dispersible PPor‐PEG NPs show good biocompatibility and biosafety, making them a promising candidate for future clinical applications in cancer theranostics.     

Renal‐Clearable PEGylated Porphyrin Nanoparticles for Image‐Guided Photodynamic Cancer Therapy

Nanomaterials with renal clearance from the body within a reasonable timescale have shown great promises in the area of nanomedicine recently. However, the integration of theranostic and renal clearance properties into a single ultrasmall nanostructure remains a great challenge. Herein, meso‐tetra(4‐carboxyphenyl)porphyrin (TCPP) structure is utilized as a model, for the first time using noninvasive dynamic positron emission tomography (PET) imaging to investigate the balance of the renal clearance and tumor uptake behaviors of polyethylene glycol (PEG)‐modified porphyrin nanoparticles (TCPP‐PEG) with various molecular weights. This study finds that TCPP‐PEG nanoparticles with larger molecular weight show higher tumor uptake due to the enhanced permeability and retention effect, while the lower ones tend to be better for renal clearance. Based on dynamic PET and fluorescence dual‐modal imaging modalities, the TCPP‐PEG_10K nanoparticles seem to be an excellent choice for the balance of renal clearance and tumor retention. In vitro and in vivo photodynamic therapy confirms an excellent therapeutic efficacy. Therefore, this work presents a simplified approach to fabricate and select biocompatible multifunctional TCPP‐PEG‐based theranostic agents with renal clearance behavior, which highlights the clinical application potential of TCPP‐PEG nanoparticles as theranostic probes for imaging‐guided cancer therapy.     

Nanostructural Control Enables Optimized Photoacoustic–Fluorescence–Magnetic Resonance Multimodal Imaging and Photothermal Therapy of Brain Tumor

The performance of current multimodal imaging contrast agents is often constrained by the tunability of nanomaterial structural design. Herein, the influence of nanostructure on the overall imaging performance of a composite nanomaterial for multimodal imaging of brain tumors is studied. Newly designed near‐infrared molecules (TC1) are encapsulated into nanocomposites with ultrasmall iron oxide nanoparticles (UIONPs), forming stable nanoagents for multimodal imaging and photothermal therapy (PTT). Through a modified nanoprecipitation method, the synthesis of nanocomposites denoted as HALF is realized, in which UIONPs are restricted to half of the nanosphere. Such a unique nanostructure that physically separates TC1 and UIONPs is found with capabilities of mitigating fluorescence quenching, preserving the good performance of photoacoustic imaging, and enhancing the magnetic resonance imaging signals. Decorated with a peptide ligand cRGD for better brain tumor targeting, HALF‐cRGD is evaluated both in vitro and in vivo as imaging contrast agents and photothermal therapeutic agents. The good imaging performance and PTT effect of HALF‐cRGD in mice models indicate that the rational design and control of nanostructures could optimize multimodal imaging performance using the same components.     

Near-Infrared Light Triggered Silk Fibroin Scaffold for Photothermal Therapy and Tissue Repair of Bone Tumors

Silk fibroin (SF) has attracted great interest in bone tissue engineering due to its extraordinary characteristics in terms of mechanical properties, biocompatibility, and biodegradability. SF scaffolds are assembled by biocompatible polydopamine nanoparticles at mesoscopic scale, which endows the scaffolds with a near-infrared (NIR) light response for the treatment of bone tumors. The functionalized SF scaffold not only enhances the significant structure and performance of native SF scaffold for bone treatment and reconstruction, such as primary and mesoscopic structure, multi-level pores, and biodegradation, as well as biocompatibility but also have excellent photothermal effect leading a significant cytotoxicity to MG63 cancer cells after NIR laser irradiation. Moreover, the penetration of NIR light in tissue is improved using an optical fiber, which demonstrates the obtained scaffolds’ great potential in the application of photothermal therapy.     

Nanoparticles of Chlorin Dimer with Enhanced Absorbance for Photoacoustic Imaging and Phototherapy

Nanoparticle assembled from organic molecules is a versatile platform to integrate various functionalities for theranostics. In this work, nanoparticles are constructed from chlorin dimers that are synthesized by reducing porphyrin molecules. Chlorin dimers can assemble into nanoscale aggregates in the absence of surfactants or other auxiliary agent. The resulting nanoparticles of chlorin dimer exhibit much higher absorbance than the porphyrin counterparts, resulting in enhanced photodynamic and photothermal activity upon irradiation. The forming nanoparticles can be effectively endocytosed by the tumor cells, inducing apoptosis under irradiation. Tumor growth on mice model is inhibited by the photodynamic and photothermal treatment in vivo. Furthermore, this nanoparticle can be used for photoacoustic imaging. It is believed that the integrated imaging and phototherapeutic capability in one nanoparticle is beneficial for future cancer diagnosis, therapy, and molecular imaging.     

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.     

Ultrafast Synthesis of Ultrasmall Poly(Vinylpyrrolidone)‐Protected Bismuth Nanodots as a Multifunctional Theranostic Agent for In Vivo Dual‐Modal CT/Photothermal‐Imaging‐Guided Photothermal Therapy

To elaborately fabricate real‐time monitoring and therapeutic function into a biocompatible nanoplatform is a promising route in the cancer therapy field. However, the package of diagnosis and treatment into a single‐“element” nanoparticle remains challenge. Herein, ultrasmall poly(vinylpyrrolidone)‐protected bismuth nanodots (PVP‐Bi nanodots) are successfully synthesized through an ultrafacile strategy (1 min only under ambient conditions). The nanodots are easy to synthesize in both laboratory and large scale using low‐cost bismuth ingredients. PVP‐Bi nanodots with ultrasmall size show good biocompatibility. Due to the high X‐ray attenuation ability of Bi element, PVP‐Bi nanodots have prominent performance on X‐ray computed tomography (CT) imaging. Moreover, PVP‐Bi nanodots exhibit a high photothermal conversion efficiency (η = 30%) because of the strong near‐infrared absorbance, which can serve as nanotheranostic agent for photothermal imaging and cancer therapy. The subsequent PVP‐Bi‐nanodot‐mediated photothermal therapy (PTT) result shows highly efficient ablation of cancer cells both in vitro and in vivo. PVP‐Bi nanodots can be almost completely excreted from mice after 7 d. Blood biochemistry and histology analysis suggests that PVP‐Bi nanodots have negligible toxicity. All the positive results reveal that PVP‐Bi nanodots produced through the ultrafacile method are promising single‐“element” nanotheranostic platform for dual‐modal CT/photothermal‐imaging‐guided PTT.