Significance Bacterial infection is the major risk to public health. Developing emissive metal–based photosensitizers against bacterial infections draws continued interest in biomedicine. The most important issue is extending the absorption and emission wavelengths of metal-based photosensitizers to ameliorate the efficiency of in vivo imaging and phototherapy. To address this, we rationally designed a long-wavelength–emissive ruthenium (II) metallacycle (herein referred to as 1) that has superior optical penetration (∼7 mm) and satisfactory reactive oxygen species–generation performance. Complex 1 has promising broad-spectrum antibacterial activity and low toxicity to mammalian cells. Moreover, 1 enables high-performance, in vivo, fluorescent imaging-guided phototherapy of Staphylococcus aureus–infected mice, with ignorable adverse effects, thus demonstrating that 1 could be a good platform for pathogen phototheranostics.

Long wavelength–emissive Ru(II) metallacycle–based photosensitizer assisting in vivo bacterial diagnosis and antibacterial treatment

Construction of a 980 nm laser-activated Pt(II) metallacycle nanosystem for efficient and safe photo-induced bacteria sterilization

Phototheranostics with second near‐infrared (NIR‐II) imaging and photothermal effect have become a burgeoning biotechnology for tumor diagnosis and precise treatment. As important parameters of phototheranostic agents (PTAs), fluorescence quantum yield (QY) and photothermal conversion efficiency (PCE) are usually considered as a pair of contradictions that is difficult to be simultaneously enhanced. Herein, a fluorination strategy for designing A–D–A type PTAs with synchronously improved QY and PCE is proposed. Experimental results show that the molar extinction coefficient (ε), NIR‐II QY, and PCE of all fluorinated PTAs nanoparticles (NPs) are definitely improved compared with the chlorinated counterparts. Theoretical calculation results demonstrate that fluorination can maximize the electrostatic potential difference by virtue of the high electronegativity of fluorine, which may increase intra/intermolecular D–A interactions, tighten molecule packing, and further promote the increase of ε, ultimately leading to simultaneously enhanced QY and PCE. In these PTA NPs, FY6‐NPs display NIR‐II emission extended to 1400 nm with the highest NIR‐II QY (4.2%) and PCE (80%). These features make FY6‐NPs perform well in high‐resolution imaging of vasculature and NIR‐II imaging‐guided photothermal therapy (PTT) of tumors. This study develops a valuable guideline for constructing NIR‐II organic PTAs with high performance.

Fluorination Enhances NIR‐II Emission and Photothermal Conversion Efficiency of Phototheranostic Agents for Imaging‐Guided Cancer Therapy

As a modern biomedical therapeutic modality, sonodynamic therapy (SDT) presents unique advantages, including superior tissue penetration capability, temporal–spatial controllability, and negligible side effects. However, the bottlenecks of most organic sonosensitizers are their short emission wavelengths, strong phototoxicity, and unsatisfactory SDT effect, which undermines the precise fluorescence imaging‐guided SDT in vivo. Here, a long‐wavelength emissive and mitochondria‐targeted organic nanosonosensitizer, named CCNU980 nanoparticles (NPs), is rationally designed, which possesses deep‐tissue optical penetration (up to 6 mm), depth‐activated ROS production (up to 8 cm), high photostability, and low phototoxicity. In vitro studies verify CCNU980 NPs selectively enriches in cancer cells with the ability to target the mitochondria and induce mitochondria‐mediated apoptosis using abundant 1O2 under US irradiation. Notably, CCNU980 NPs enables precise in vivo NIR‐II fluorescence imaging‐guided SDT, accompanied by the suppression of the bilateral 4T1 tumor growth with minimal side effects. The current work can inspire a general strategy for the design of organic nanosonosensitizers with long‐wavelength emission and new thoughts for precision medicine.

Construction of Long‐Wavelength Emissive Organic Nanosonosensitizer Targeting Mitochondria for Precise and Efficient In Vivo Sonotherapy

Cancer remains a severe threat to human health. To date, although various therapeutic methods, including radiotherapy (RT), chemotherapy, chemodynamic therapy (CDT), phototherapy, starvation therapy, and immunotherapy, have entered a new stage of rapid progress in cancer theranostics, their limited therapeutic effect and significant side effects need to be considered carefully. With the rapid development of nanotechnology, the marriage of nanomaterials and therapeutic methods provides the practical possibility to improve the deficiencies in cancer therapy. Notably, metal-organic frameworks (MOFs) composed of ions/clusters and bridging ligands through coordination bonds have been widely applied in cancer therapy to deal with the drawbacks of different therapeutic methods, such as severe side effects, low stability, and poor efficacy, owing to their controllable morphologies, tailorable diameters, diverse compositions, tunable porosities, high specific surface areas, facile functionalization, and good biocompatibility. This review summarizes the recent advanced developments and achievements of multifunctional MOF-based nanoplatforms for cancer therapy through single therapy methods, including RT, chemotherapy, CDT, phototherapy (photodynamic and photothermal therapy), starvation therapy and immunotherapy, and combination therapy methods. Moreover, the prospects and challenges of MOF-based nanoplatforms used in tumor therapy are also discussed.

Multifunctional metal-organic framework (MOF)-based nanoplatforms for cancer therapy: from single to combination therapy

Although Ru(II)-based agents are expected to be promising candidates for substituting Pt-drug, their in vivo biomedical applications are still limited by the short excitation/emission wavelengths and unsatisfactory therapeutic efficiency. Herein, we rationally design a Ru(II) metallacycle with excitation at 808 nm and emission over 1000 nm, namely Ru1085, which holds deep optical penetration (up to 6 mm) and enhanced chemo-phototherapy activity. In vitro studies indicate that Ru1085 exhibits prominent cell uptake and desirable anticancer capability against various cancer cell lines, especially for cisplatin-resistant A549 cells. Further studies reveal Ru1085 induces mitochondria-mediated apoptosis along with S and G2/M phase cell cycle arrest. Finally, Ru1085 shows precise NIR-II fluorescence imaging guided and long-term monitored chemo-phototherapy against A549 tumor with minimal side effects. We envision that the design of long-wavelength emissive metallacycle will offer emerging opportunities of metal-based agents for in vivo biomedical applications. 

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Construction of emissive ruthenium(II) metallacycle over 1000 nm wavelength for in vivo biomedical applications

ZIF-8, as an important photoresponsive metal-organic framework (MOF), holds great promise in the field of cancer theranostics owing to its versatile physiochemical properties. However, its photocatalytic anticancer application is still restricted because of the wide bandgap and specific response to ultraviolet light. Herein, we developed lanthanide-doped nanoparticles (LDNPs) coated with Fe/Mn bimetal-doped ZIF-8 (LDNPs@Fe/Mn-ZIF-8) for second near-infrared (NIR-II) imaging-guided synergistic photodynamic/chemodynamic therapy (PDT/CDT). The LDNPs were synthesized by encapsulating an optimal Yb3+/Ce3+-doped active shell on the NaErF4:Tm core to achieve dual-mode red upconversion (UC) and NIR-II downconversion (DC) emission upon NIR laser irradiation. At the optimal doping concentration, the UC and DC NIR-II emission intensities of LDNPs were increased 30.2- and 13.2-fold above those of core nanoparticles, which endowed LDNPs@Fe/Mn-ZIF-8 with an outstanding capability to carry out UC-mediated PDT and NIR-II optical imaging. In addition, the dual doping of Fe2+/Mn2+ markedly decreased the bandgap of the ZIF-8 photosensitizer from 5.1 to 1.7 eV, expanding the excitation threshold of ZIF-8 to the visible light region (∼650 nm), which enabled Fe/Mn-ZIF-8 to be efficiently excited by UC photons to achieve photocatalytic-driven PDT. Furthermore, Fe2+/Mn2+ ions could be responsively released in the tumor microenvironment through degradation of Fe/Mn-ZIF-8, thereby producing hydroxyl radicals (·OH) by Fenton/Fenton-like reactions to realize CDT. Meanwhile, the degradation of Fe/Mn-ZIF-8 endowed the nanosystems with tumor self-enhanced NIR-II imaging function, providing precise guidance for CDT/PDT.

Fe/Mn Bimetal-Doped ZIF-8-Coated Luminescent Nanoparticles with Up/Downconversion Dual-Mode Emission for Tumor Self-Enhanced NIR-II Imaging and Catalytic Therapy.

Single‐atom nanozymes (SAzymes) can effectively mimic the metal active centers of natural enzymes at the atomic level owing to their atomically dispersed active sites, thereby maximizing atom utilization efficiency and density of active sites. Hence, SAzymes can be considered the most promising candidates to replace natural enzymes. Herein, a PEGylated mesoporous Mn‐based single‐atom nanozyme (PmMn/SAE) employing a coordination‐assisted polymerization pyrolysis strategy that uses polydopamine for photothermal‐augmented nanocatalytic therapy is designed. PmMn/SAE exhibits excellent multiple enzymatic performance, including catalase‐like, oxidase‐like, and peroxidase (POD)‐like performance, due to the atomically dispersed Mn active species. As a result, PmMn/SAE not only catalyzes the decomposition of endogenous H2O2 to generate O2 for relieving hypoxia inside the tumor but also transfers electrons to O2 to produce superoxide radicals to kill tumor cells. Meanwhile, PmMn/SAE is able to trigger Fenton‐like reactions to generate highly toxic hydroxyl radicals to induce cancer cell apoptosis. The POD‐like catalytic mechanism of mMn/SAE is revealed using experimental results and density functional theory. Furthermor, PmMn/SAE shows good photothermal conversion efficiency (η = 22.1%) in the second near‐infrared region (1064 nm). Both the in vitro and in vivo experimental results indicate that PmMn/SAE can effectively kill cancer cells through photothermal‐enhanced catalytic therapy.

Tumor Response and NIR‐II Photonic Thermal Co‐Enhanced Catalytic Therapy Based on Single‐Atom Manganese Nanozyme

Biomimetic nanozyme with natural enzyme-like activities has drawn extensive attention in cancer therapy, while its application was hindered by the limited catalytic efficacy in the complicated tumor microenvironment (TME). Herein, a hybrid biomimetic nanozyme combines polydopamine-decorated CuO with a natural enzyme of glucose oxidase (GOD), among which CuO is endowed with a high loading rate (47.1%) of GOD due to the elaborately designed hollow mesoporous structure that is constructed to maximize the cascade catalytic efficacy. In the TME, CuO could catalyze endogenous H2O2 into O2 for relieving tumor hypoxia and improving the catalytic efficacy of GOD. Whereafter, the amplified glucose oxidation induces starvation therapy, and the generated H2O2 and H+ enhance the catalytic activity of CuO. Significantly, the tumor-specific chemodynamic therapy (CDT) could be realized when CuO degraded into Cu2+ in acidic and reductive TME. Furthermore, the photothermal therapy with high photothermal conversion efficiency (30.2%) is achieved under NIR-II laser (1064 nm) excitation, which could reinforce the generation of reactive oxygen species (•OH and •O2-). The TME initiates the biochemical reaction cycle of CuO, O2, and GOD, which couples with an NIR-II-induced thermal effect to realize O2-promoted starvation and photothermal-chemodynamic combined therapy. This hybrid biomimetic nanozyme enlightens the further development of nanozymes in multimodal cancer therapy.

Biomimetic Nanoarchitectonics of Hollow Mesoporous Copper Oxide-Based Nanozymes with Cascade Catalytic Reaction for Near Infrared-II Reinforced Photothermal-Catalytic Therapy.

Chemodynamic therapy (CDT) and photodynamic therapy (PDT) based on intratumoral generation of reactive oxygen species (ROS) have been playing crucial roles in conquering tumors. However, the above therapeutic methods are still constrained by the overexpressed tumor glutathione (GSH) and intrinsic tumor resistance to conventional organic photosensitizers. Herein, lanthanide-doped nanoparticles (LDNPs) were coated with inorganic bimetallic copper and manganese silicate nanospheres (CMSNs) and modified with sodium alginate (SA) for second near-infrared (NIR-II, 1000-1700 nm) imaging-guided CDT and PDT. Interestingly, cross-relaxation (CR) pathways between Ce3+ and Ho3+ and CR between Ce3+ and Er3+ are fully exploited to enable dual-mode upconversion (UC) and NIR-II downconversion (DC) emissions of LDNPs under 980 nm laser excitation. UC emission can induce CMSNs to produce toxic singlet oxygen (1O2) for PDT, and the released Mn2+ and Cu+ ions caused by GSH-induced degradation of CMSNs can react with endogenous H2O2 to produce hydroxyl radical (˙OH) for CDT. Significantly, the ultrabright NIR-II DC emission endows the systems with exceptional optical imaging capabilities. All results affirm the potency of such an "all in one" theranostic nanomedicine integrating PDT, CDT and remarkable NIR-II imaging abilities accompanied by the function of modulating tumor microenvironment in cancer theranostics.

Shuang Liu

Papers

Construction of emissive ruthenium(II) metallacycle over 1000 nm wavelength for in vivo biomedical applications

Fe/Mn Bimetal-Doped ZIF-8-Coated Luminescent Nanoparticles with Up/Downconversion Dual-Mode Emission for Tumor Self-Enhanced NIR-II Imaging and Catalytic Therapy.

Tumor Response and NIR‐II Photonic Thermal Co‐Enhanced Catalytic Therapy Based on Single‐Atom Manganese Nanozyme

Biomimetic Nanoarchitectonics of Hollow Mesoporous Copper Oxide-Based Nanozymes with Cascade Catalytic Reaction for Near Infrared-II Reinforced Photothermal-Catalytic Therapy.

Tumor-responsive nanomedicine based on Ce3+-modulated up-/downconversion dual-mode emission for NIR-II imaging-guided dynamic therapy.