Dual‐Stage‐Light‐Guided Tumor Inhibition by Mitochondria‐Targeted Photodynamic Therapy

In this paper, a self‐delivery system PpIX‐PEG‐(KLAKLAK)₂ (designated as PPK) is fabricated to realize mitochondria‐targeted photodynamic tumor therapy. It is found that the PPK self‐delivery system exhibited high drug loading efficacy as well as novel capacity in generation of intracellular reactive oxygen species (ROS). This study also indicated that the photochemical internalization effect of the photosensitizer protoporphyrin IX (PpIX) under a short time light irradiation improved the cellular internalization of PPK. On the contrary, PPK could target to the subcellular organelle mitochondria due to the presence of proapoptosis (KLAKLAK)₂ peptide. Importantly, the in situ generation of ROS in mitochondria enhanced the photodynamic therapy efficacy under another long time irradiation, leading to significant cell death with decreased mitochondrial membrane potential. Besides, relative high tumor accumulation, minimal systemic cytotoxicity and efficacious long‐term tumor inhibition in vivo are also confirmed by using a murine model. All these results demonstrated the self‐delivery system PPK with a dual‐stage light irradiation strategy is a promising nanoplatform for tumor treatment.     

Photoacoustic Imaging Guided Near‐Infrared Photothermal Therapy Using Highly Water‐Dispersible Single‐Walled Carbon Nanohorns as Theranostic Agents

The poly(maleic anhydride‐alt‐1‐octadecene‐poly(ethylene glycol)) (C₁₈PMH‐PEG) modified single‐walled carbon nanohorns (SWNHs) are designed with high stability and biocompatibility. The as‐prepared SWNHs/C₁₈PMH‐PEG not only can serve as an excellent photothermal agent but also can be used as a promising photoacoustic imaging (PAI) agent both in vitro and in vivo due to its strong absorption in the near infrared (NIR) region. The PAI result reveals that the SWNHs/C₁₈PMH‐PEG possesses ultra long blood circulation time and can significantly be accumulated at the tumor site through the enhanced penetration and retention (EPR) effect. The maximum accumulation of SWNHs/C₁₈PMH‐PEG at tumor site could be achieved at the time point of 24 h after intravenous injection, which is considered to be the optimal time for the 808 nm laser treatment. The subsequent photothermal ablation of tumors can be achieved without triggering any side effects. Therefore, a PAI guided PTT platform based on SWNHs is proposed and highlights the potential theranostic application for biomedical uses.     

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.     

Smart Tumor Microenvironment‐Responsive Nanotheranostic Agent for Effective Cancer Therapy

The tumor microenvironment (TME), which includes acidic and hypoxic conditions, severely impedes the therapeutic efficacy of antitumor agents. Herein, MnO₂‐loaded, bovine serum albumin, and PEG co‐modified mesoporous CaSiO₃ nanoparticles (CaM‐PB NPs) are developed as a nanoplatform with sequential theranostic functions for the engineering of TME. The MnO₂ NPs generate O₂ in situ by reacting with endogenous H₂O₂, relieving the hypoxic state of the TME that further modulates the cancer cell cycle status to S phase, which improves the potency of co‐loaded S phase‐sensitive chemotherapeutic drugs. After the hypoxia relief, CaM‐PB can sustainably release drugs due to the enlarged pores of mesoporous CaSiO₃ in the acidic TME, preventing the drug pre‐leakage into the blood circulation and insufficient drug accumulation at tumor sites. Moreover, the Mn²⁺ released from the MnO₂ NPs at tumor sites can potentially serve as a diagnostic agent, enabling the identification of tumor regions by T₁‐weighted magnetic resonance imaging during therapy. In vivo pharmacodynamics results demonstrate that these synergetic effects caused by CaM‐PB NPs significantly contribute to the inhibition of tumor progression. Therefore, the CaM‐PB NPs with sequential theranostic functions are a promising system for effective cancer therapy.     

BSA‐Mediated Synthesis of Bismuth Sulfide Nanotheranostic Agents for Tumor Multimodal Imaging and Thermoradiotherapy

Fabrication of ultrasmall single‐component omnipotent nanotheranostic agents integrated with multimodal imaging and multiple therapeutic functions becomes more and more practically relevant but challenging. In this article, sub 10 nm Bi₂S₃ biocompatible particles are prepared through a bovine serum albumin (BSA)‐mediated biomineralization process under ambient aqueous conditions. Owing to the ultrasmall size and colloidal stability, the resulting nanoparticles (NPs) present outstanding blood circulation behavior and excellent tumor targeting ability. Toward theranostic applications, the biosafety profile is carefully investigated. In addition, photothermal conversion is characterized for both photoacoustic imaging and photothermal treatment of cancers. Upon radiolabeling, the performance of the resulting particles for SPECT/CT imaging in vivo is also carried out. Additionally, different combinations of treatments are applied for evaluating the performance of the as‐prepared Bi₂S₃ NPs in photothermal‐ and radiotherapy of tumors. Due to the remarkable photothermal conversion efficiency and large X‐ray attenuation coefficient, the implanted tumors are completely eradicated through combined therapies, which highlights the potential of BSA‐capped Bi₂S₃ NPs as a novel multifunctional nanotheranostic agent.     

Optimization of Prussian Blue Coated NaDyF4:x%Lu Nanocomposites for Multifunctional Imaging‐Guided Photothermal Therapy

Imaging‐guided photothermal therapy based on functional nanomaterials has recently received significant attention and the selection of functional materials with optimal imaging and therapy effect is extremely important. In this work, NaDyF₄‐based nanoparticles with varying size are synthesized by doping with different amounts of lutetium ions. To obtain an optimized material, the influence factor of magnetic resonance, X‐ray attenuation, and photothermal properties are discussed in detail. Then, NaDyF₄:50%Lu@Prussian blue (PB) nanocomposite is selected as the optimal functional material for T₁‐ and T₂‐weighted magnetic resonance imaging, X‐ray computed tomography, and photothermal imaging‐guided photothermal therapy of tumor on a small animal model, and the treatment is applied with good results. Studies also suggest that the NaDyF₄:50%Lu@PB nanocomposites are biocompatibile. The selection of an optimal material from a multi‐perspective study has provided an incentive for the development of an assortment of novel multifunctional materials for early cancer multifunctional diagnosis and imaging‐guided photothermal therapy.     

Designer Exosomes for Active Targeted Chemo‐Photothermal Synergistic Tumor Therapy

Exosomes, naturally derived nanovesicles secreted from various cell types, can serve as an effective platform for the delivery of various cargoes, because of their intrinsic ability such as long blood circulation and immune escapinge. However, unlike conventional synthetic nanoparticles, drug release from exosomes at defined targets is not controllable. Moreover, endowing exosomes with satisfactory cancer‐targeting ability is highly challenging. Here, for the first time, a biological and synthetic hybrid designer exosome is described with photoresponsive functionalities based on a donor cell‐assisted membrane modification strategy. Practically, the designer exosome effectively accumulates at target tumor sites via dual ligand‐mediated endocytosis. Then the localized hyperthermia induced by the conjunct gold nanorods under near‐infrared irradiation impacts the permeability of exosome membrane to enhance drug release from exosomes, thus inhibiting tumor relapse in a programmable manner. The designer exosome combines the merits of both synthetic materials and the natural nanovesicles. It not only preserves the intrinsic functionalities of native exosome, but also gains multiple abilities for efficient tumor targeting, controlled release, and thermal therapy like synthetic nanocarriers. The versatile designer exosome can provide functional platforms by engineering with more multifarious functionalities from synthetic materials to achieve individualized precise cancer therapy in the future.     

All‐in‐One Phototheranostics: Single Laser Triggers NIR‐II Fluorescence/Photoacoustic Imaging Guided Photothermal/Photodynamic/Chemo Combination Therapy

Development of single near‐infrared (NIR) laser triggered phototheranostics for multimodal imaging guided combination therapy is highly desirable but is still a big challenge. Herein, a novel small‐molecule dye DPP‐BT is designed and synthesized, which shows strong absorption in the first NIR window (NIR‐I) and fluorescence emission in the second NIR region (NIR‐II). Such a dye not only acts as a dual‐modal contrast agent for NIR‐II fluorescence and photoacoustic (PA) imaging, but also serves as a combined therapeutic agent for photothermal therapy (PTT) and photodynamic therapy (PDT). The single NIR laser triggered all‐in‐one phototheranostic nanoparticles are constructed by encapsulating the dye DPP‐BT, chemotherapy drug DOX, and natural phase‐change materials with a folic acid functionalized amphiphile. Notably, under NIR laser irradiation, DOX can effectively release from such nanoparticles via NIR‐induced hyperthermia of DPP‐BT. By intravenous injection of such nanoparticles into Hela tumor‐bearing mice, the tumor size and location can be accurately observed via NIR‐II fluorescence/PA dual‐modal imaging. From in vitro and in vivo therapy results, such nanoparticles simultaneously present remarkable antitumor efficacy by PTT/PDT/chemo combination therapy, which is triggered by a single NIR laser. Overall, this work provides an innovative strategy to design and construct all‐in‐one nanoplatforms for clinical phototheranostics.     

Mixed-Metal MOF-Derived Hollow Porous Nanocomposite for Trimodality Imaging Guided Reactive Oxygen Species-Augmented Synergistic Therapy

Here an excellent trimodality imaging-guided synergistic photothermal therapy (PTT)/photodynamic therapy (PDT)/chemodynamic therapy (CDT) is proposed. To this end, a mixed-metal Cu/Zn-metal-organic framework (MOF) is first assembled at room temperature on a nano-scale. Interestingly, heating the MOF results in a Cu^+/2+-coexisting hollow porous structure. Subsequent heating treatment is used to integrate Mn²⁺ and MnO₂ in the presence of manganese(II) acetylacetonate. The hollow composite achieves efficient loading of a photosensitizer, indocyanine green (ICG). Under laser irradiation, the aggregated ICG achieves photothermal imaging and PTT. Once released in the tumor site, ICG exhibits fluorescence imaging and PDT capacity. Cu⁺/Mn²⁺ ions perform Fenton-like reaction with H₂O₂ to produce cytotoxic •OH for the enhanced CDT. Cu²⁺/MnO₂ scavenge glutathione to improve the reactive oxygen species-based therapy, while the formed Mn²⁺ ions enable “turn on” magnetic resonance imaging. Significantly, O₂ is produced from the catalytic decomposition of endogenous H₂O₂ to improve ICG-mediated PDT. Moreover, photothermal-induced local hyperthermia accelerates •OH generation to enhance CDT. This synergistic drug-free antitumor strategy realizes high treatment efficacy and low side effects on normal tissues. Thus, this mixed-metal MOF is an efficient strategy to realize hollow structures for multi-function integration to improve therapeutic capacity.     

Biocompatible PEG‐Chitosan@Carbon Dots Hybrid Nanogels for Two‐Photon Fluorescence Imaging,Near‐Infrared Light/pH Dual‐Responsive Drug Carrier,and Synergistic Therapy

This work designs a class of biocompatible PEG‐chitosan@CDs hybrid nanogels by integrating nonlinear poly(ethylene glycol) (PEG), chitosan, and graphitic carbon dots (CDs) into a single nanoparticle for two‐photon fluorescence (TPF) bioimaging, pH and near‐infrared (NIR) light dual‐responsive drug release, and synergistic therapy. Such hybrid nanogels can be simply prepared from a one‐pot surfactant‐free precipitation polymerization of the PEG macromonomers complexed with chitosan and CDs in water, resulting in a semi‐interpenetration of chitosan chains and an immobilization of CDs in the nonlinear PEG networks. The embedded CDs in hybrid nanogels not only serve as an excellent confocal and TPF imaging contrast agent and fluorescent pH‐sensing probe, but also enhance the loading capacity of the hybrid nanogels for hydrophobic anticancer drug. The chitosan can induce a pH‐sensitive swelling/deswelling of the hybrid nanogels for pH‐regulated drug release over the physiologically important range of 5.0–7.4 and surface modulation of embedded CDs to realize fluorescent pH sensing. The thermosensitive nonlinear PEG network can promote the drug release through the local heat produced by the embedded CDs under NIR irradiation. The in vitro results indicate that the hybrid nanogels demonstrated high therapeutic efficacy through the synergistic effect of combined chemo–photothermal treatments.     

High‐Security Multifunctional Nano‐Bismuth‐Sphere‐Cluster Prepared from Oral Gastric Drug for CT/PA Dual‐Mode Imaging and Chemo‐Photothermal Combined Therapy In Vivo

Multifunctional nanoprobes that can be applied for real‐time monitoring or precision treatment of tumors have received wide interest among researchers. However, most of these nanoprobes are obtained through chemical synthesis, and thereby may contain toxic residues or harmful reagents. In this article, a nano‐bismuth‐sphere‐cluster (Bi) is synthesized via a one‐step method (after an irradiation with ultra‐violet) and is then applied in dual‐mode computed tomography/photoacoustic imaging. Bismuth potassium citrate granules, which is a common gastric drug that is highly safe and has a low price (<1 China Yuan/g), is used as the only raw material. The results show that the Bi cluster has good stability with sizes of about 25–55 nm, and a photothermal conversion efficiency as high as 39.67%. After being adsorbed onto doxorubicin, the Bi cluster can be used directly in animal experiments. Due to the effect of enhanced permeability and retention, the probe can easily enter tumor cells. Drug release can be controlled by a near‐infrared laser and the acidic environment of tumor cells, which indicates that the combined chemo‐photothermal therapy is achieved. This work presents a new dual‐mode bio‐imaging and combined chemo‐photothermal therapeutic nanoprobe that can be applied in theragnostics for tumors.     

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.     

Gold Nanoframeworks with Mesopores for Raman–Photoacoustic Imaging and Photo‐Chemo Tumor Therapy in the Second Near‐Infrared Biowindow

Gold‐based nanostructures with tunable wavelength of localized surface plasmon resonance (LSPR) in the second near‐infrared (NIR‐II) biowindow receive increasing attention in phototheranostics. In view of limited progress on NIR‐II gold nanostructures, a particular liposome template‐guided route is explored to synthesize novel gold nanoframeworks (AuNFs) with large mesopores (≈40 nm) for multimodal imaging along with therapeutic robustness. The synthesized AuNFs exhibit strong absorbance in NIR‐II region, affording their capacity of NIR‐II photothermal therapy (PTT) and photoacoustic (PA) imaging for deep tumors. Functionalization of AuNFs with hyaluronic acid (HA) endows the targeting capacity for CD44‐overexpressed tumor cells while gatekeeping doxorubicin (DOX) loaded into mesopores. Conjugation of Raman reporter 4‐aminothiophenol (4‐ATP) onto AuNFs yields a surface‐enhanced Raman scattering (SERS) fingerprint for Raman spectroscopy/imaging. In vivo evaluation of HA‐4‐ATP‐AuNFs‐DOX on tumor‐bearing xenografts demonstrates its high efficacy in eradication of solid tumors in NIR‐II under PA–Raman dual image‐guided photo‐chemotherapy. Thus, current AuNFs offer versatile capabilities for phototheranostics.     

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.     

An Integrated Multifunctional Nanoplatform for Deep‐Tissue Dual‐Mode Imaging

The combination of biocompatible superparamagnetic and photoluminescent nanoparticles (NPs) is intensively studied as highly promising multifunctional (magnetic confinement and targeting, imaging, etc.) tools in biomedical applications. However, most of these hybrid NPs exhibit low signal contrast and shallow tissue penetration for optical imaging due to tissue‐induced optical extinction and autofluorescence, since in many cases, their photoluminescent components emit in the visible spectral range. Yet, the search for multifunctional NPs suitable for high photoluminescence signal‐to‐noise ratio, deep‐tissue imaging is still ongoing. Herein, a biocompatible core/shell/shell sandwich structured Fe₃O₄@SiO₂@NaYF₄:Nd³⁺ nanoplatform possessing excellent superparamagnetic and near‐infrared (excitation) to near‐infrared (emission), i.e., NIR‐to‐NIR photoluminescence properties is developed. They can be rapidly magnetically confined, allowing the NIR photoluminescence signal to be detected through a tissue as thick as 13 mm, accompanied by high T₂ relaxivity in magnetic resonance imaging. The fact that both the excitation and emission wavelengths of these NPs are in the optically transparent biological windows, along with excellent photostability, fast magnetic response, significant T₂‐contrast enhancement, and negligible cytotoxicity, makes them extremely promising for use in high‐resolution, deep‐tissue dual‐mode (optical and magnetic resonance) in vivo imaging and magnetic‐driven applications.     

Mesoporous Polydopamine Carrying Manganese Carbonyl Responds to Tumor Microenvironment for Multimodal Imaging‐Guided Cancer Therapy

Multifunctional nanodrugs integrating multiple therapeutic and imaging functions may find tremendous biomedical applications. However, the development of a simple yet potent theranostic nanosystem with a high payload and microenvironment responsiveness enhancing imaging‐guided cancer therapy is still a great challenge. Herein, a kind of MnCO‐entrapped mesoporous polydopamine nanoparticles are developed, which reach a 1.5 mg payload per gram carrier and exhibit marked theranostic capability through effective CO/Mn²⁺ generation and photothermal conversion inside the H⁺ and H₂O₂‐enriched tumor microenvironment, for a magnetic resonance/photoacoustic bimodal imaging‐guided tumor therapy. The multifunctional nanosystem exhibits a biocompatibility highly desirable for in vivo application and superior performance in inhibiting tumor growth and recurrence via combination CO and photothermal therapy.     

Cell Membrane Camouflaged Hollow Prussian Blue Nanoparticles for Synergistic Photothermal‐/Chemotherapy of Cancer

Nanodrug‐based cancer therapy has been actively developed in the past decades. The main challenges faced by nanodrugs include poor drug loading capacity, rapid clearance from blood circulation, and low antitumor efficiency with high risk of recurrence. In this work, red blood cell (RBC) membrane camouflaged hollow mesoporous Prussian blue nanoparticles (HMPB@RBC NPs) are fabricated for combination therapy of cancer. The stability, immune evading capacity, and blood retention time of HMPB@RBC NPs are significantly enhanced compared with those of bare HMPB NPs. Doxorubicin (DOX), as a model drug is encapsulated within HMPB@RBC NPs with loading capacity up to 130% in weight. In addition, DOX loaded HMPB@RBC NPs show pH‐/photoresponsive release. The in vivo studies demonstrate the outstanding performance of DOX@HMPB@RBC NPs in synergistic photothermal‐/chemotherapy of 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.