Metallo-Dye-Based Supramolecular Nanoassembly for NIR-II Cancer Theranostics.

Retaining intrinsic photophysical performance and efficient therapeutic efficacy of cyanine dyes in the second near-infrared (NIR-II) biowindow are challenges in the biomedical field. Herein, we develop a metal ion-assisted NIR-II fluorophore assembly strategy to modulate molecular arrangement behavior, thus overcoming the drawbacks and retaining the photophysical performance of cyanine dyes in aqueous media for cancer phototheranostics. By screening a series of metal ion-assisted fluorophore assemblies, we remarkably found gadolinium-based metallo-dye-supramolecular nanoassembly (denoted as Gd@IR1064) with the intrinsic optical properties of NIR-II cyanine dye (IR1064). Most intriguingly, the as-prepared Gd@IR1064 not only exhibits deep-tissue-penetrating NIR-II photoacoustic, fluorescence, and magnetic resonance imaging ability but also possesses enhanced photothermal conversion performance-induced hyperthermia, achieving a significant tumor elimination effect. Our study provides a promising guide for modulating dye arrangement with unique photophysical performance for biomedical applications.

In vivo three-dimensional multispectral photoacoustic imaging of dual enzyme-driven cyclic cascade reaction for tumor catalytic therapy.

Non-invasive visualization of dynamic molecular events in real-time via molecular imaging may enable the monitoring of cascade catalytic reactions in living systems, however effective imaging modalities and a robust catalytic reaction system are lacking. Here we utilize three-dimensional (3D) multispectral photoacoustic (PA) molecular imaging to monitor in vivo cascade catalytic therapy based on a dual enzyme-driven cyclic reaction platform. The system consists of a two-dimensional (2D) Pd-based nanozyme conjugated with glucose oxidase (GOx). The combination of nanozyme and GOx can induce the PA signal variation of endogenous molecules. Combined with the PA response of the nanozyme, we can simultaneously map the 3D PA signals of dynamic endogenous and exogenous molecules associated with the catalytic process, thus providing a real-time non-invasive visualization. We can also treat tumors under the navigation of the PA imaging. Therefore, our study demonstrates the imaging-guided potential of 3D multispectral PA imaging in feedback-looped cascade catalytic therapy.

Enzyme-Engineered Conjugated Polymer Nanoplatform for Activatable Companion Diagnostics and Multistage Augmented Synergistic Therapy.

Companion diagnostics (CDx) provides critical information for precision medicine. However, current CDx is mostly limited to in vitro tests, which cannot accurately evaluate the disease progression and treatment response in real time. To overcome this challenge, herein a glucose oxidase (GOx)-engineered conjugated polymer (polyaniline, PANI) nanoplatform (denoted as PANITG) is reported for activatable imaging-based CDx and multistage augmented photothermal/starvation synergistic therapy. PANITG comprises a pH-activatable conjugated polymer as a photothermal convertor and photoacoustic (PA) emitter, a GOx as a cancer starvation inducer as well as a H2 O2 and acid producer, and a H2 O2 -cleavable linker as a "switch" for GOx activity. The in vivo PA imaging and photothermal therapy abilities are activated by acidic tumor microenvironment and self-augmented by the reaction between GOx and glucose. Meanwhile, the photothermal effect will enhance the GOx activity in turn. Such multistage augmentation of the therapeutic effects will facilitate effective cancer management. In addition, the in vivo PA imaging with PANITG reveals the tumor pH level which is correlated to the efficiency of the photothermal therapy and to the catalytic activity of GOx at each stage, enabling real-time activatable CDx.

Engineering Bacteria and Bionic Bacterial Derivatives with Nanoparticles for Cancer Therapy.

Natural bacteria are interesting subjects for cancer treatments owing to their unique autonomy-driven and hypoxic target properties. Genetically modified bacteria (such as bacteria with msbB gene and aroA gene modifications) can effectively cross sophisticated physiological barriers and transport antitumor agents into deep tumor tissues, and they have good biosafety. Additionally, bacteria can secrete cytokines (such as interleukin-224, interferon-gamma [IFN-γ], and interleukin-1ß) and activate antitumor immune responses in the tumor microenvironment, resulting in tumor inhibition. All of these characteristics can be easily utilized to develop synergistic antitumor strategies by combining bacteria-based agents with other therapeutic approaches. Herein, representative studies of bacteria-instructed multimodal synergistic cancer therapy are introduced (e.g., photothermal therapy, chemoimmunotherapy, photodynamic therapy, and photocontrolled bacterial metabolite therapy), and their key advantages are systematically expounded. The current challenges and future prospects in advancing the development of bacteria-based micro/nanomedicines in the field of synthetic biology research are also emphasized, which will hopefully promote the development of related bacteria-based cancer therapies.

In Situ Sprayed Starvation/Chemodynamic Therapeutic Gel for Post-Surgical Treatment of IDH1 (R132H) Glioma.

Complete resection of isocitrate dehydrogenase 1 (IDH1) (R132H) glioma is unfeasible and the classic post-surgical chemo/radiotherapy suffers from high recurrence and low survival rate. IDH1 (R132H) cells are sensitive to low concentrations of glucose and high concentrations of reactive oxygen species (ROS) due to inherent metabolism reprograming. Hence, a starvation/chemodynamic therapeutic gel is developed to combat residual IDH1 (R132H) tumor cells after surgery. Briefly, glucose oxidase (GOx) is mineralized with manganese-doped calcium phosphate to form GOx@MnCaP nanoparticles, which are encapsulated into the fibrin gel (GOx@MnCaP@fibrin). After spraying gel in the surgical cavity, GOx catalyzes the oxidation of glucose in residual IDH1 (R132H) cells and produces H2 O2 . The generated H2 O2 is further converted into highly lethal hydroxyl radicals (•OH) by a Mn2+ -mediated Fenton-like reaction to further kill the residual IDH1 (R132H) cells. The as-prepared starvation/chemodynamic therapeutic gel shows much higher therapeutic efficacy toward IDH1 (R132H) cells than IDH1 (WT) cells, and achieves long-term survival.

Chemotherapeutic drug-DNA hybrid nanostructures for anti-tumor therapy.

Compared to traditional drug delivery systems, DNA nanostructure-based drug delivery systems have several advantages including programmable sequences, precise size and shape, high drug payloads, excellent biocompatibility and biodegradability. To date, a wide range of chemotherapeutic drug-DNA hybrid nanostructures have been developed for anti-tumor therapy. In this review, the constructions of various DNA nanostructures for anticancer drug delivery are firstly summarized. Next, the anticancer drug loading methods for DNA nanostructures are presented. Then, the recent applications of chemotherapeutic drug-DNA hybrid nanostructures for drug delivery are highlighted. In the end, the challenges and opportunities of the chemotherapeutic drug-DNA hybrid nanostructure-based delivery system are discussed. The designs of drug-DNA hybrid systems, including the constructions of nanostructures and the strategies for drug loading, largely influence the efficiency of drug delivery. Recent studies have focused on the development of novel drug-DNA hybrid systems to acquire more precise and efficient therapy for various diseases. A systematic review of the design strategies of chemotherapeutic drug-DNA hybrid nanostructures will benefit the innovation and development of the chemotherapeutic drug-based chemotherapy in clinics.

Multifunctional Magnesium Organic Framework-Based Microneedle Patch for Accelerating Diabetic Wound Healing.

Diabetic wound healing is one of the major challenges in the biomedical fields. The conventional single drug treatments have unsatisfactory efficacy, and the drug delivery effectiveness is restricted by the penetration depth. Herein, we develop a magnesium organic framework-based microneedle patch (denoted as MN-MOF-GO-Ag) that can realize transdermal delivery and combination therapy for diabetic wound healing. Multifunctional magnesium organic frameworks (Mg-MOFs) are mixed with poly(γ-glutamic acid) (γ-PGA) hydrogel and loaded into the tips of MN-MOF-GO-Ag, which slowly releases Mg2+ and gallic acid in the deep layer of the dermis. The released Mg2+ induces cell migration and endothelial tubulogenesis, while gallic acid, a reactive oxygen species-scavenger, promotes antioxidation. Besides, the backing layer of MN-MOF-GO-Ag is made of γ-PGA hydrogel and graphene oxide-silver nanocomposites (GO-Ag) which further enables excellent antibacterial effects for accelerating wound healing. The therapeutic effects of MN-MOF-GO-Ag on wound healing are demonstrated with the full-thickness cutaneous wounds of a diabetic mouse model. The significant improvement of wound healing is achieved for mice treated with MN-MOF-GO-Ag.

Weaving Enzymes with Polymeric Shells for Biomedical Applications.

Enzyme therapeutics have received increasing attention due to their high biological specificity, outstanding catalytic efficiency, and impressive therapeutic outcomes. Protecting and delivering enzymes into target cells while retaining enzyme catalytic efficiency is a big challenge. Wrapping of enzymes with rational designed polymer shells, rather than trapping them into large nanoparticles such as liposomes, have been widely explored because they can protect the folded state of the enzyme and make post-functionalization easier. In this review, the methods for wrapping up enzymes with protective polymer shells are mainly focused on. It is aimed to provide a toolbox for the rational design of polymeric enzymes by introducing methods for the preparation of polymeric enzymes including physical adsorption and chemical conjugation with specific examples of these conjugates/hybrid applications. Finally, a conclusion is drawn and key points are emphasized.

Dual-Stimuli-Responsive Nanotheranostics for Dual-Targeting Photothermal-Enhanced Chemotherapy of Tumor.

Stimuli-responsive nanotheranostics have been widely explored for precision medicine. Here, we developed a pH/light dual-stimuli-responsive nanotheranostic agent for biological/physical dual-targeting photothermal-enhanced chemotherapy of U87MG tumor. This nanotheranostic agent was composed of the RGD (Arg-Gly-Asp) peptide, melanin-coated magnetic nanoparticles (MMNs), doxorubicin (DOX), and indocyanine green (ICG), denoted as RMDI. The tumor accumulation of RMDI was simultaneously improved through biological active targeting by RGD and physical magnetic targeting by an external magnetic field at tumor tissues, which was proven by in vivo photoacoustic/magnetic resonance/fluorescence (PA/MR/FL) trimodal imaging. Under dual stimuli of the tumor acidic microenvironment and laser irradiation, both DOX and ICG were released in a controlled fashion, demonstrating impressive therapeutic outcomes against U87MG tumor both in vitro and in vivo, respectively. Owing to the synergistic photothermal/chemotherapy, the dual-stimuli-responsive and dual-targeting nanotheranostic agent completely ablated U87MG tumor in vivo without any tumor recurrence and biotoxicity. This nanotheranostic agent exhibited great potential in multimodal imaging-guided synergistic therapy of cancer.

Tumor-Specific Activatable Nanocarriers with Gas-Generation and Signal Amplification Capabilities for Tumor Theranostics.

Multifunctional nanotheranostics are typically designed by integrating multiple functional components. This approach not only complicates the preparation process but also hinders any bioapplication due to the potential toxic effects when each component is metabolized. Here, we report a safe, biodegradable, and tumor-specific nanocarrier that, once activated by the acidic tumor microenvironment (TME), has diagnostic and therapeutic functions suitable for tumor theranostics. Our nanocarrier is composed of biomineralized manganese carbonate (BMC) nanoparticles (NPs) that readily decompose to release Mn2+ ions and CO2 gas in the acidic TME due to its intrinsic pH-dependent solubility. Mn2+ and CO2 release permits magnetic resonance and ultrasound imaging of tumors, respectively. These NPs can be loaded with the anticancer drug doxorubicin (DOX): BMC-DOX has high tumor inhibition effects both in vitro and in vivo due to combined Mn2+-mediated chemodynamic therapy and DOX-induced chemotherapy. This tumor-specific actuating nanocarrier might be a promising candidate for clinical translation.

Light-Triggered Transformable Ferrous Ion Delivery System for Photothermal Primed Chemodynamic Therapy.

Chemodynamic therapy (CDT) involves the catalytic generation of highly toxic hydroxyl radicals (. OH) from hydrogen peroxide (H2 O2 ) through metal-ion-mediated Fenton or Fenton-like reactions. Fe2+ is a classical catalyst ion, however, it suffers easy oxidation and systemic side-effects. Therefore, the development of a controllable Fe2+ delivery system is a challenge to maintain its valence state, reduce toxicity, and improve therapeutic efficacy. Reported here is a near-infrared (NIR) light-triggered Fe2+ delivery agent (LET-6) for fluorescence (FL) and photoacoustic (PA) dual-modality imaging guided, photothermal primed CDT. Thermal expansion caused by 808 nm laser irradiation triggers the transformation of LET-6 to expose Fe2+ from its hydrophobic layer, which primes the catalytic breakdown of endogenous H2 O2 within the tumor microenvironment, thus generating . OH for enhanced CDT. LET-6 shows remarkable therapeutic effects, both in vitro and in vivo, achieving 100 % tumor elimination after just one treatment. This high-performance Fe2+ delivery system provides a sound basis for future synergistic metal-ion-mediated cancer therapy.

Recent Advances in Self-Exciting Photodynamic Therapy.

Photodynamic therapy (PDT) is already (Food and Drug Administration) FDA approved and used in the clinic for oncological treatment of pancreatic, lung, esophagus, bile duct, and of course several cancers of skin. It is an important tool in the oncological array of treatments, but for it exist several shortcomings, the most prominent of which is the shallow depth penetration of light within tissues. One-way researchers have attempted to circumvent this is through the creation of self-exciting "auto-PDT" nanoplatforms, which do not require the presence of an external light source to drive the PDT process. Instead, these platforms are driven either through oxidative chemical excitation in the form of chemiluminescence or radiological excitation from beta-emitting isotopes in the form of Cherenkov luminescence. In both, electronic excitations are generated and then transferred to the photosensitizer (PS) via Resonance Energy Transfer (RET) or Cherenkov Radiation Energy Transfer (CRET). Self-driven PDT has many components, so in this review, using contemporary examples from literature, we will breakdown the important concepts, strategies, and rationale behind the design of these self-propagating PDT nanoplatforms and critically review the aspects which make them successful and different from conventional PDT. Particular focus is given to the mechanisms of excitation and the different methods of transfer of excited electronic energy to the photosensitizer as well as the resulting therapeutic effect. The papers reviewed herein will be critiqued for their apparent therapeutic efficiency, and a basic rationale will be developed for what qualities are necessary to constitute an "effective" auto-PDT platform. This review will take a biomaterial engineering approach to the review of the auto-PDT platforms and the intended audience includes researchers in the field looking for a new perspective on PDT nanoplatforms as well as other material scientists and engineers looking to understand the mechanisms and relations between different parts of the complex "auto-PDT" system.

Recent Advances in Croconaine Dyes for Bioimaging and Theranostics.

Croconaine (CR) dyes, the donor-acceptor-donor (D-A-D) type zwitterionic compounds with extended π-conjugation, can be readily synthesized via a straightforward condensation reaction. They have received much attention in bioimaging and theranostics, owing to their tailored structures and fascinating near-infrared (NIR) photophysical properties. In this topical review, we summarize the recent advances in biomedical applications for CR dyes. First, we introduce the classification and optical performance of CR dyes. Next, we highlight the chemistry and applications of CR dyes in bioimaging and theranostics. Finally, the summary and prospects of CR dyes for bioimaging and theranostics are discussed.

Biomimetic hybrid membrane-based nanoplatforms: synthesis, properties and biomedical applications.

The rapid clearance and capture by the immune system pose a big challenge in targeted drug delivery using nanocarriers. Cell membrane coating endows nanoplatforms with prolonged blood circulation, enhanced immune escape, and improved targeting capability. However, monotypic cell membrane fails to meet the omnifarious needs of biomedical applications. The combination of different types of cell membranes provides a promising solution to provide multifunctional biomimetic nanoplatforms. In this review, we first discuss the feasibility of constructing biomimetic hybrid membranes and summarize current methods of preparing biomimetic hybrid membrane-based nanoplatforms (BHMNs) and their biomedical applications including drug delivery, cancer detection, detoxification, and cancer vaccines. Finally, the prospects and challenges of utilizing BHMNs for personalized medicine are also discussed.

Ultrasound-Enhanced Chemo-Photodynamic Combination Therapy by Using Albumin "Nanoglue"-Based Nanotheranostics.

The combination of photodynamic therapy (PDT) and chemotherapy is considered to enhance the antitumor immunity and combat multidrug resistance. Some preclinical studies have reported a positive therapeutic outcome of using ultrasound (US) irradiation to enhance chemotherapy, but the combination of these three modalities has yet to be investigated. On the basis of the discovery of a strong affinity between a photosensitizer sinoporphyrin sodium (DVDMS) and human serum albumin (HSA), a clinically used albumin-paclitaxel (HSA-PTX) nanoparticle is utilized as a "nanoglue" to load a large amount of DVDMS by simple mixing. The five conformations of HSA and DVDMS with highest affinity were calculated using AutoDock Vina. The obtained albumin "nanoglue"-based nanotheranostics, HSA-PTX-DVDMS (HPD), has better fluorescence imaging and PDT performance than free DVDMS, probably due to the reduced quenching of DVDMS after dispersion in albumin. An efficacious tumor-targeting enhancement of chemotherapy by US irradiation is verified in a bilateral subcutaneous 4T1 tumors model. With the aid of US irradiation, the combined PDT and chemotherapy mediated by HPD achieve effective tumor growth inhibition. Overall, this "nanoglue"-based nanotheranostics is composed of several clinically used elements and integrates three clinical modalities with application prospects in clinic.

Biomaterial scaffold-based local drug delivery systems for cancer immunotherapy.

Immunotherapy has attracted tremendous attention due to the remarkable clinical successes for treating a broad spectrum of tumors. One challenge for cancer immunotherapy is the inability to control localization and sustain concentrations of therapeutics at tumor sites. Local drug delivery systems (LDDSs) like the biomaterial scaffold-based drug delivery systems have emerged as a promising approach for delivering immunotherapeutic agents facilely and intensively in situ with reduced systemic toxicity. In this review, recent advances in biomaterial scaffold-based LDDSs for the administration of immunotherapeutic agents including vaccines, immunomodulators, and immune cells are summarized. Moreover, co-delivery systems are also evaluated for local immunotherapy-involving combination anti-tumor therapy, including chemotherapy-immunotherapy, photothermal-immunotherapy, and other combination therapies. Finally, the current challenges and future perspectives on the development of next-generation LDDSs for cancer immunotherapy are discussed.