A Mesoporous Nanoenzyme Derived from Metal–Organic Frameworks with Endogenous Oxygen Generation to Alleviate Tumor Hypoxia for Significantly Enhanced Photodynamic Therapy

Tumor hypoxia compromises the therapeutic efficiency of photodynamic therapy (PDT) as the local oxygen concentration plays an important role in the generation of cytotoxic singlet oxygen (¹O₂). Herein, a versatile mesoporous nanoenzyme (NE) derived from metal–organic frameworks (MOFs) is presented for in situ generation of endogenous O₂ to enhance the PDT efficacy under bioimaging guidance. The mesoporous NE is constructed by first coating a manganese‐based MOFs with mesoporous silica, followed by a facile annealing process under the ambient atmosphere. After removing the mesoporous silica shell and post‐modifying with polydopamine and poly(ethylene glycol) for improving the biocompatibility, the obtained mesoporous NE is loaded with chlorin e6 (Ce6), a commonly used photosensitizer in PDT, with a high loading capacity. Upon the O₂ generation through the catalytic reaction between the catalytic amount NE and the endogenous H₂O₂, the hypoxic tumor microenvironment is relieved. Thus, Ce6‐loaded NE serves as a H₂O₂‐activated oxygen supplier to increase the local O₂ concentration for significantly enhanced antitumor PDT efficacy in vitro and in vivo. In addition, the NE also shows T₂‐weighted magnetic resonance imaging ability for its in vivo tracking. This work presents an interesting biomedical use of MOF‐derived mesoporous NE as a multifunctional theranostic agent in cancer therapy.     

Dual‐Stage Light Amplified Photodynamic Therapy against Hypoxic Tumor Based on an O2 Self‐Sufficient Nanoplatform

Tumor hypoxia severely limits the efficacy of traditional photodynamic therapy (PDT). Here, a liposome‐based nanoparticle (designated as LipoMB/CaO₂) with O₂ self‐sufficient property for dual‐stage light‐driven PDT is demonstrated to address this problem. Through a short time irradiation, ¹O₂ activated by the photosensitizer methylene blue (MB) can induce lipid peroxidation to break the liposome, and enlarge the contact area of CaO₂ with H₂O, resulting in accelerated O₂ production. Accelerated O₂ level further regulates hypoxic tumor microenvironment and in turn improves ¹O₂ generation by MB under another long time irradiation. In vitro and in vivo experiments also demonstrate the superior competence of LipoMB/CaO₂ to alleviate tumor hypoxia, suppress tumor growth and antitumor metastasis with low side‐effect. The O₂ self‐sufficient LipoMB/CaO₂ nanoplatform with dual‐stage light manipulation is a successful attempt for PDT against hypoxic tumor.     

Gadolinium‐Encapsulated Graphene Carbon Nanotheranostics for Imaging‐Guided Photodynamic Therapy

Photosensitizers (PS) are an essential component of photodynamic therapy (PDT). Conventional PSs are often porphyrin derivatives, which are associated with high hydrophobicity, low quantum yield in aqueous solutions, and suboptimal tumor‐to‐normal‐tissue (T/N) selectivity. There have been extensive efforts to load PSs into nanoparticle carriers to improve pharmacokinetics. The approach, however, is often limited by PS self‐quenching, pre‐mature release, and nanoparticle accumulation in the reticuloendothelial system organs. Herein, a novel, nanoparticle‐based PS made of gadolinium‐encapsulated graphene carbon nanoparticles (Gd@GCNs), which feature a high ¹O₂ quantum yield, is reported. Meanwhile, Gd@GCNs afford strong fluorescence and high T₁ relaxivity (16.0 × 10^?3m ^?1 s^?1, 7 T), making them an intrinsically dual‐modal imaging probe. Having a size of approximately 5 nm, Gd@GCNs can accumulate in tumors through the enhanced permeability and retention effect. The unbound Gd@GCNs cause little toxicity because Gd is safely encapsulated within an inert carbon shell and because the particles are efficiently excreted from the host through renal clearance. Studies with rodent tumor models demonstrate the potential of the Gd@GCNs to mediate image‐guided PDT for cancer treatment. Overall, the present study shows that Gd@GCNs possess unique physical, pharmaceutical, and toxicological properties and are an all‐in‐one nanotheranostic tool with substantial clinical translation potential.     

Au Nanoclusters Sensitized Black TiO2−x Nanotubes for Enhanced Photodynamic Therapy Driven by Near‐Infrared Light

The low reactive oxygen species production capability and the shallow tissue penetration of excited light (UV) are still two barriers in photodynamic therapy (PDT). Here, Au cluster anchored black anatase TiO_2?x nanotubes (abbreviated as Au₂₅/B‐TiO_2?x NTs) are synthesized by gaseous reduction of anatase TiO₂ NTs and subsequent deposition of noble metal. The Au₂₅/B‐TiO_2?x NTs with thickness of about 2 nm exhibit excellent PDT performance. The reduction process increased the density of Ti³⁺ on the surface of TiO₂, which effectively depresses the recombination of electron and hole. Furthermore, after modification of Au₂₅ nanoclusters, the PDT efficiency is further enhanced owing to the changed electrical distribution in the composite, which forms a shallow potential well on the metal–TiO₂ interface to further hamper the recombination of electron and hole. Especially, the reduction of anatase TiO₂ can expend the light response range (UV) of TiO₂ to the visible and even near infrared (NIR) light region with high tissue penetration depth. When excited by NIR light, the nanoplatform shows markedly improved therapeutic efficacy attributed to the photocatalytic synergistic effect, and promotes separation or restrained recombination of electron and hole, which is verified by experimental results in vitro and in vivo.     

Near‐Infrared Upconversion Mesoporous Cerium Oxide Hollow Biophotocatalyst for Concurrent pH‐/H2O2‐Responsive O2‐Evolving Synergetic Cancer Therapy

Tumor hypoxia is typically presented in the central region of solid tumors, which is mainly caused by an inadequate blood flow and oxygen supply. In the conventional treatment of hypoxic human tumors, not only the oxygen‐dependent photodynamic therapy (PDT), but also antitumor drug‐based chemotherapy, is considerably limited. The use of direct oxygen delivering approach with oxygen‐dependent PDT or chemotherapy may potentiate the reactive oxygen species (ROS)‐mediated cytotoxicity of the drug toward normal tissues. Herein, a synergetic one‐for‐all mesoporous cerium oxide upconversion biophotocatalyst is developed to achieve intratumorally endogenous H₂O₂‐responsive self‐sufficiency of O₂ and near‐infrared light controlled PDT simultaneously for overcoming hypoxia cancer. Furthermore, the sufficient O₂ plays an important role in overcoming the chemotherapeutic drug‐resistant cancer caused by hypoxia, therefore inducing tumor cell apoptosis significantly.     

Surface Plasmon Resonance–Enhanced Photoacoustic Imaging and Photothermal Therapy of Endogenous H2S‐Triggered Au@Cu2O

Smart theranostics agents triggered by endogenous H₂S with combined activated photoacoustic imaging and photothermal therapy can improve the diagnosis and treatment of colon cancer. However, the low theranostic performance of the current smart theranostics agents after the triggering step has limited their further application. In this work, the theranostic performance of endogenous H₂S‐triggered Au@Cu₂O for the diagnosis and treatment of colon cancer, which is generated from the localized surface plasmon resonance coupling effect between a noble metal (Au) and a semiconductor (Cu₂O), is investigated. Compared with Cu₂O, the prepared H₂S‐triggered Au@Cu₂O shows a significantly stronger absorption at the near‐infrared region, such as a ≈2.1 times change at 808 nm, giving a photothermal conversion efficiency increase of ≈1.2 times. More importantly, Au@Cu₂O still exhibits good photoacoustic imaging contrast and photothermal properties for treatment of colon cancer in vivo even at very low injection doses. This work not only investigates an endogenous H₂S‐triggered Au@Cu₂O theranostic agent with enhanced theranostic performance for colon cancer but also provides a novel strategy for designing high‐performance theranostic agents.     

Photosensitive Nanoparticles Combining Vascular‐Independent Intratumor Distribution and On‐Demand Oxygen‐Depot Delivery for Enhanced Cancer Photodynamic Therapy

In drug delivery, the poor tumor perfusion results in disappointing therapeutic efficacy. Nanomedicines for photodynamic therapy (PDT) greatly need deep tumor penetration due to short lifespan and weak diffusion of the cytotoxic reactive oxygen species (ROS). The damage of only shallow cells can easily cause invasiveness and metastasis. Moreover, even if the nanomedicines enter into deeper lesion, the effectiveness of PDT is limited due to the hypoxic microenvironment. Here, a deep penetrating and oxygen self‐sufficient PDT nanoparticle is developed for balanced ROS distribution within tumor and efficient cancer therapy. The designed nanoparticles (CNPs/IP) are doubly emulsified (W/O/W) from poly(ethylene glycol)‐poly(ε‐caprolactone) copolymers doped with photosensitizer IR780 in the O layer and oxygen depot perfluorooctyl bromide (PFOB) inside the core, and functionalized with the tumor penetrating peptide Cys‐Arg‐Gly‐Asp‐Lys (CRGDK). The CRGDK modification significantly improves penetration depth of CNPs/IP and makes the CNPs/IP arrive at both the periphery and hypoxic interior of tumors where the PFOB releases oxygen, effectively alleviating hypoxia and guaranteeing efficient PDT performance. The improved intratumoral distribution of photosensitizer and adequate oxygen supply augment the sensitivity of tumor cells to PDT and significantly improve PDT efficiency. Such a nanosystem provides a potential platform for improved therapeutic index in anticancer therapy.     

Manganese Dioxide Coated WS2@Fe3O4/sSiO2 Nanocomposites for pH‐Responsive MR Imaging and Oxygen‐Elevated Synergetic Therapy

Recently, the development of multifunctional theranostic nanoplatforms to realize tumor‐specific imaging and enhanced cancer therapy via responding or modulating the tumor microenvironment (TME) has attracted tremendous interests in the field of nanomedicine. Herein, tungsten disulfide (WS₂) nanoflakes with their surface adsorbed with iron oxide nanoparticles (IONPs) via self‐assembly are coated with silica and then subsequently with manganese dioxide (MnO₂), on to which polyethylene glycol (PEG) is attached. The obtained WS₂‐IO/S@MO‐PEG appears to be highly sensitive to pH, enabling tumor pH‐responsive magnetic resonance imaging with IONPs as the pH‐inert T2 contrast probe and MnO₂ as the pH‐sensitive T1 contrast probe. Meanwhile, synergistic combination tumor therapy is realized with such WS₂‐IO/S@MO‐PEG, by utilizing the strong near‐infrared light and X‐ray absorbance of WS₂ for photothermal therapy (PTT) and enhanced cancer radiotherapy (RT), respectively, as well as the ability of MnO₂ to decompose tumor endogenous H₂O₂ and relieve tumor hypoxia to further overcome hypoxia‐associated radiotherapy resistance. The combination of PTT and RT with WS₂‐IO/S@MO‐PEG results in a remarkable synergistic effect to destruct tumors. This work highlights the promise of developing multifunction nanocomposites for TME‐specific imaging and TME modulation, aiming at precision cancer synergistic treatment.     

Tumor Microenvironment‐Triggered Aggregation of Antiphagocytosis 99mTc‐Labeled Fe3O4 Nanoprobes for Enhanced Tumor Imaging In Vivo

A tumor microenvironment responsive nanoprobe is developed for enhanced tumor imaging through in situ crosslinking of the Fe₃O₄ nanoparticles modified with a responsive peptide sequence in which a tumor‐specific Arg‐Gly‐Asp peptide for tumor targeting and a self‐peptide as a “mark of self” are linked through a disulfide bond. Positioning the self‐peptide at the outmost layer is aimed at delaying the clearance of the nanoparticles from the bloodstream. After the self‐peptide is cleaved by glutathione within tumor microenvironment, the exposed thiol groups react with the remaining maleimide moieties from adjacent particles to crosslink the particles in situ. Both in vitro and in vivo experiments demonstrate that the aggregation substantially improves the magnetic resonance imaging (MRI) contrast enhancement performance of Fe₃O₄ particles. By labeling the responsive particle probe with ^99mTc, single‐photon emission computed tomography is enabled not only for verifying the enhanced imaging capacity of the crosslinked Fe₃O₄ particles, but also for achieving sensitive dual modality imaging of tumors in vivo. The novelty of the current probe lies in the combination of tumor microenvironment‐triggered aggregation of Fe₃O₄ nanoparticles for boosting the T₂ MRI effect, with antiphagocytosis surface coating, active targeting, and dual‐modality imaging, which is never reported before.     

Rational Design of Multifunctional Fe@γ‐Fe2O3@H‐TiO2 Nanocomposites with Enhanced Magnetic and Photoconversion Effects for Wide Applications: From Photocatalysis to Imaging‐Guided Photothermal Cancer Therapy

Titanium dioxide (TiO₂) has been widely investigated and used in many areas due to its high refractive index and ultraviolet light absorption, but the lack of absorption in the visible–near infrared (Vis–NIR) region limits its application. Herein, multifunctional Fe@γ‐Fe₂O₃@H‐TiO₂ nanocomposites (NCs) with multilayer‐structure are synthesized by one‐step hydrogen reduction, which show remarkably improved magnetic and photoconversion effects as a promising generalists for photocatalysis, bioimaging, and photothermal therapy (PTT). Hydrogenation is used to turn white TiO₂ in to hydrogenated TiO₂ (H‐TiO₂), thus improving the absorption in the Vis–NIR region. Based on the excellent solar‐driven photocatalytic activities of the H‐TiO₂ shell, the Fe@γ‐Fe₂O₃ magnetic core is introduced to make it convenient for separating and recovering the catalytic agents. More importantly, Fe@γ‐Fe₂O₃@H‐TiO₂ NCs show enhanced photothermal conversion efficiency due to more circuit loops for electron transitions between H‐TiO₂ and γ‐Fe₂O₃, and the electronic structures of Fe@γ‐Fe₂O₃@H‐TiO₂ NCs are calculated using the Vienna ab initio simulation package based on the density functional theory to account for the results. The reported core–shell NCs can serve as an NIR‐responsive photothermal agent for magnetic‐targeted photothermal therapy and as a multimodal imaging probe for cancer including infrared photothermal imaging, magnetic resonance imaging, and photoacoustic imaging.