Polyphenol‐Inspired Facile Construction of Smart Assemblies for ATP‐ and pH‐Responsive Tumor MR/Optical Imaging and Photothermal Therapy

Smart assemblies have attracted increased interest in various areas, especially in developing novel stimuli‐responsive theranostics. Herein, commercially available, natural tannic acid (TA) and iron oxide nanoparticles (Fe₃O₄ NPs) are utilized as models to construct smart magnetic assemblies based on polyphenol‐inspired NPs–phenolic self‐assembly between NPs and TA. Interestingly, the magnetic assemblies can be specially disassembled by adenosine triphosphate, which shows a stronger affinity to Fe₃O₄ NPs than that of TA and partly replaces the surface coordinated TA. The disassembly can further be facilitated by the acidic environment hence causing the remarkable change of the transverse relaxivity and potent “turn‐on” of fluorescence (FL) signals. Therefore, the assemblies for specific and sensitive tumor magnetic resonance and FL dual‐modal imaging and photothermal therapy after intravenous injection of the assemblies are successfully employed. This work not only provides understandings on the self‐assembly between NPs and polyphenols, but also will open new insights for facilely constructing versatile assemblies and extending their biomedical applications.     

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.     

A Full‐Spectrum Metal‐Free Porphyrin Supramolecular Photocatalyst for Dual Functions of Highly Efficient Hydrogen and Oxygen Evolution

A full‐spectrum (300–700 nm) responsive porphyrin supramolecular photocatalyst with a theoretical solar spectrum efficiency of 44.4% is successfully constructed. For the first time, hydrogen and oxygen evolution (40.8 and 36.1 µmol g^?1 h^?1) is demonstrated by a porphyrin photocatalyst without the addition of any cocatalysts. The strong oxidizing performance also presents an efficient photodegradation activity that is more than ten times higher than that of g‐C₃N₄ for the photodegradation of phenol. The high photocatalytic reduction and oxidation activity arises from a strong built‐in electric field due to molecular dipoles of electron‐trapping groups and the nanocrystalline structure of the supramolecular photocatalyst. The appropriate band structure of the supramolecular photocatalyst adjusted via the highest occupied molecular orbital and lowest unoccupied molecular orbital energy levels of the porphyrin gives rise to thermodynamic driving potential for H₂ and O₂ evolution under visible light irradiation. Controlling the energy band structure of photocatalysts via the ordered assembly of structure‐designed organic molecules could provide a novel approach for the design of organic photocatalysts in energy and environmental applications.     

Bioresponsive Microneedles with a Sheath Structure for H2O2 and pH Cascade‐Triggered Insulin Delivery

Self‐regulating glucose‐responsive insulin delivery systems have great potential to improve clinical outcomes and quality of life among patients with diabetes. Herein, an H₂O₂‐labile and positively charged amphiphilic diblock copolymer is synthesized, which is subsequently used to form nano‐sized complex micelles (NCs) with insulin and glucose oxidase of pH‐tunable negative charges. Both NCs are loaded into the crosslinked core of a microneedle array patch for transcutaneous delivery. The microneedle core is additionally coated with a thin sheath structure embedding H₂O₂‐scavenging enzyme to mitigate the injury of H₂O₂ toward normal tissues. The resulting microneedle patch can release insulin with rapid responsiveness under hyperglycemic conditions owing to an oxidative and acidic environment because of glucose oxidation, and can therefore effectively regulate blood glucose levels within a normal range on a chemically induced type 1 diabetic mouse model with enhanced biocompatibility.     

A Singlet Oxygen Generating Agent by Chirality‐dependent Plasmonic Shell‐Satellite Nanoassembly

Photodynamic therapy (PDT) agent, which generates singlet oxygen (¹O₂) under light, has attracted significant attention for its broad biological and medical applications. Here, DNA‐driven shell–satellite (SS) gold assemblies as chiral photosensitizers are first fabricated. The chiral plasmonic nanostructure, coupling with cysteine enantiomers on its surface, exhibits intense chiroplasmonic activities (?40.2 ± 2.6 mdeg) in the visible region. These chiral SS nanoassemblies have high reactive oxygen species generating efficiency under circular polarized light illumination, resulting in a ¹O₂ quantum yield of 1.09. Meanwhile, it is found that SS could be utilized as PDT agent with remarkable efficiency under right circular polarized light irradiation in vitro and in vivo, allowing X‐ray computed tomography (CT) and photoacoustics (PA) imaging for tumors simultaneously. The achievements reveal that the enantiomer‐dependent and structure‐induced nanoassemblies play an important role in PDT effects. The present researches open up a new avenue for cancer diagnose and therapy using chiral nanostructures as multifunctional platform.     

Suppressing Surface Lattice Oxygen Release of Li‐Rich Cathode Materials via Heterostructured Spinel Li4Mn5O12 Coating

Lithium‐rich layered oxides with the capability to realize extraordinary capacity through anodic redox as well as classical cationic redox have spurred extensive attention. However, the oxygen‐involving process inevitably leads to instability of the oxygen framework and ultimately lattice oxygen release from the surface, which incurs capacity decline, voltage fading, and poor kinetics. Herein, it is identified that this predicament can be diminished by constructing a spinel Li₄Mn₅O₁₂ coating, which is inherently stable in the lattice framework to prevent oxygen release of the lithium‐rich layered oxides at the deep delithiated state. The controlled KMnO₄ oxidation strategy ensures uniform and integrated encapsulation of Li₄Mn₅O₁₂ with structural compatibility to the layered core. With this layer suppressing oxygen release, the related phase transformation and catalytic side reaction that preferentially start from the surface are consequently hindered, as evidenced by detailed structural evolution during Li⁺ extraction/insertion. The heterostructure cathode exhibits highly competitive energy‐storage properties including capacity retention of 83.1% after 300 cycles at 0.2 C, good voltage stability, and favorable kinetics. These results highlight the essentiality of oxygen framework stability and effectiveness of this spinel Li₄Mn₅O₁₂ coating strategy in stabilizing the surface of lithium‐rich layered oxides against lattice oxygen escaping for designing high‐performance cathode materials for high‐energy‐density lithium‐ion batteries.     

DNA‐Assembled Core‐Satellite Upconverting‐Metal–Organic Framework Nanoparticle Superstructures for Efficient Photodynamic Therapy

DNA‐mediated assembly of core–satellite structures composed of Zr(IV)‐based porphyrinic metal‐organic framework (MOF) and NaYF₄,Yb,Er upconverting nanoparticles (UCNPs) for photodynamic therapy (PDT) is reported. MOF NPs generate singlet oxygen (¹O₂) upon photoirradiation with visible light without the need for additional small molecule, diffusional photosensitizers such as porphyrins. Using DNA as a templating agent, well‐defined MOF–UCNP clusters are produced where UCNPs are spatially organized around a centrally located MOF NP. Under NIR irradiation, visible light emitted from the UCNPs is absorbed by the core MOF NP to produce ¹O₂ at significantly greater amounts than what can be produced from simply mixing UCNPs and MOF NPs. The MOF–UCNP core–satellite superstructures also induce strong cell cytotoxicity against cancer cells, which are further enhanced by attaching epidermal growth factor receptor targeting affibodies to the PDT clusters, highlighting their promise as theranostic photodynamic agents.     

Stimulus‐Responsive Anti‐Oxidizing Drug Crystals and their Ecological Implication

Various antioxidants are being used to neutralize the harmful effects of reactive oxygen species (ROS) overproduced in diseased tissues and contaminated environments. Polymer‐directed crystallization of antioxidants has attracted attention as a way to control drug efficacy through molecular dissolution. However, most recrystallized antioxidants undertake continuous dissolution independent of the ROS level, thus causing side‐effects. This study demonstrates a unique method to assemble antioxidant crystals that modulate their dissolution rate in response to the ROS level. We hypothesized that antioxidants recrystallized using a ROS‐labile polymer would be triggered to dissolve when the ROS level increases. We examined this hypothesis by using catechin as a model antioxidant. Catechin was recrystallized using polyethylenimine cross‐linked with ROS‐labile diselanediylbis‐(ethane‐2,1‐diyl)‐diacrylate. Catechin crystallized with the ROS‐labile polymer displays accelerated dissolution proportional to the H₂O₂ concentration. The ROS‐responsive catechin crystals protect vascular cells from oxidative insults by activating intracellular glutathione peroxidase expression and, in turn, inhibiting an increase in the intracellular oxidative stress. In addition, ROS‐responsive catechin crystals alleviate changes in the heart rate of Daphnia magna in oxidative media. We propose that the results of this study would be broadly useful for improving the therapeutic efficacy of a broad array of drug compounds.     

Invasion and Defense Interactions between Enzyme‐Active Liquid Coacervate Protocells and Living Cells

The design and construction of mutual interaction models between artificial microsystems and living cells have the potential to open a wide range of novel applications in biomedical and biomimetic technologies. In this study, an artificial form of invasion‐defense mutual interactions is established in a community of glucose oxidase (GOx)‐containing liquid coacervate microdroplets and living cells, which interact via enzyme‐mediated reactive oxygen species (ROS) damage. The enzyme‐containing coacervate microdroplets, formed via liquid–liquid phase separation, act as invader protocells to electrostatically bind with the host HepG2 cell, resulting in assimilation. Subsequently, the glucose oxidation in the liquid coacervates initiates the generation of H₂O₂, which serves as an ROS resource to block cell proliferation. As a defense strategy, introduction of catalase (CAT) into the host cells is exploited to resist the ROS damage. CAT‐mediated decomposition of H₂O₂ leads to the ROS scavenging and results in the recovery of cell viability. The results obtained in the current study highlight the remarkable opportunities for the development of mutual interacting communities on the interface of artificial protocells/living cells. They also provide a new approach for engineering cellular behaviors through exploiting artificial nonliving microsystems.     

Self‐Assembled Pd@CeO2/γ‐Al2O3 Catalysts with Enhanced Activity for Catalytic Methane Combustion

Pd@CeO₂/Al₂O₃ catalysts are of great importance for real applications, such as three‐way catalysis, CO oxidation, and methane combustion. In this article, the Pd@CeO₂ core@shell nanospheres are prepared via the autoredox reaction in aqueous phase. Three kinds of methods are then employed, that is, electrostatic interaction, supramolecular self‐assembly, and physical mixing, to support the as‐prepared Pd@CeO₂ nanospheres on γ‐Al₂O₃. A model reaction of catalytic methane‐combustion is employed here to evaluate the three Pd@CeO₂/γ‐Al₂O₃ samples. As a result, the sample Pd@CeO₂‐S‐850 prepared via supramolecular self‐assembly and calcined at 850 °C exhibits superior catalytic performance to the others, which has a far lower light‐off temperature (T₅₀ of about 364 °C). Moreover, almost no deterioration of Pd@CeO₂‐S‐850 is observed after five sequent catalytic cycles. The analysis of H₂‐TPR curves concludes that there exists hydrogen spillover related to the strong metal–support interaction between Pd species and oxides. The strong metal–support interaction and the specific surface areas might be responsible for the catalytic performance of the Pd@CeO₂ samples toward catalytic methane combustion.     

Multifunctional pDNA‐Conjugated Polycationic Au Nanorod‐Coated Fe3O4 Hierarchical Nanocomposites for Trimodal Imaging and Combined Photothermal/Gene Therapy

It is very desirable to design multifunctional nanocomposites for theranostic applications via flexible strategies. The synthesis of one new multifunctional polycationic Au nanorod (NR)‐coated Fe₃O₄ nanosphere (NS) hierarchical nanocomposite (Au@pDM/Fe₃O₄) based on the ternary assemblies of negatively charged Fe₃O₄ cores (Fe₃O₄‐PDA), polycation‐modified Au nanorods (Au NR‐pDM), and polycations is proposed. For such nanocomposites, the combined near‐infrared absorbance properties of Fe₃O₄‐PDA and Au NR‐pDM are applied to photoacoustic imaging and photothermal therapy. Besides, Fe₃O₄ and Au NR components allow the nanocomposites to serve as MRI and CT contrast agents. The prepared positively charged Au@pDM/Fe₃O₄ also can complex plasmid DNA into pDNA/Au@pDM/Fe₃O₄ and efficiently mediated gene therapy. The multifunctional applications of pDNA/Au@pDM/Fe₃O₄ nanocomposites in trimodal imaging and combined photothermal/gene therapy are demonstrated using a xenografted rat glioma nude mouse model. The present study demonstrates that the proper assembly of different inorganic nanoparticles and polycations is an effective strategy to construct new multifunctional theranostic systems.     

Metalloporphyrin Complex‐Based Nanosonosensitizers for Deep‐Tissue Tumor Theranostics by Noninvasive Sonodynamic Therapy

Metal complexes are widely used as anticancer drugs, while the severe side effects of traditional chemotherapy require new therapeutic modalities. Sonodynamic therapy (SDT) provides a significantly noninvasive ultrasound (US) treatment approach by activating sonosensitizers and initiating reactive oxygen species (ROS) to damage malignant tissues. In this work, three metal 4‐methylphenylporphyrin (TTP) complexes (MnTTP, ZnTTP, and TiOTTP) are synthesized and encapsulated with human serum albumin (HSA) to form novel nanosonosensitizers. These nanosonosensitizers generate abundant singlet oxygen (¹O₂) under US irradiation, and importantly show excellent US‐activatable abilities with deep‐tissue depths up to 11 cm. Compared to ZnTTP‐HSA and TiOTTP‐HSA, MnTTP‐HSA exhibits the strongest ROS‐activatable behavior due to the lowest highest occupied molecular orbital?lowest unoccupied molecular orbital gap energy by density functional theory. It is also effective for deep‐tissue photoacoustic/magnetic resonance dual‐modal imaging to trace the accumulation of nanoparticles in tumors. Moreover, MnTTP‐HSA intriguingly achieves high SDT efficiency for simultaneously suppressing the growth of bilateral tumors away from ultrasound source in mice. This work develops a deep‐tissue imaging‐guided SDT strategy through well‐defined metalloporphyrin nanocomplexes and paves a new way for highly efficient noninvasive SDT treatments of malignant tumors.     

Toxic Reactive Oxygen Species Enhanced Synergistic Combination Therapy by Self‐Assembled Metal‐Phenolic Network Nanoparticles

Engineering functional nanomaterials with high therapeutic efficacy and minimum side effects has increasingly become a promising strategy for cancer treatment. Herein, a reactive oxygen species (ROS) enhanced combination chemotherapy platform is designed via a biocompatible metal‐polyphenol networks self‐assembly process by encapsulating doxorubicin (DOX) and platinum prodrugs in nanoparticles. Both DOX and platinum drugs can activate nicotinamide adenine dinucleotide phosphate oxidases, generating superoxide radicals (O₂^??). The superoxide dismutase‐like activity of polyphenols can catalyze H₂O₂ generation from O₂^??. Finally, the highly toxic HO^? free radicals are generated by a Fenton reaction. The ROS HO^? can synergize the chemotherapy by a cascade of bioreactions. Positron emission tomography imaging of ⁸⁹Zr‐labeled as‐prepared DOX@Pt prodrug Fe³⁺ nanoparticles (DPPF NPs) shows prolonged blood circulation and high tumor accumulation. Furthermore, the DPPF NPs can effectively inhibit tumor growth and reduce the side effects of anticancer drugs. This study establishes a novel ROS promoted synergistic nanomedicine platform for cancer therapy.     

Glutathione Depletion in a Benign Manner by MoS2‐Based Nanoflowers for Enhanced Hypoxia‐Irrelevant Free‐Radical‐Based Cancer Therapy

Tumor hypoxia significantly diminishes the efficacy of reactive oxygen species (ROS)‐based therapy, mainly because the generation of ROS is highly oxygen dependent. Recently reported hypoxia‐irrelevant radical initiators (AIBIs) exhibit promising potential for cancer therapy under different oxygen tensions. However, overexpressed glutathione (GSH) in cancer cells would potently scavenge the free radicals produced from AIBI before their arrival to the specific site and dramatically limit the therapeutic efficacy. A synergistic antitumor platform (MoS₂@AIBI‐PCM nanoflowers) is constructed by incorporating polyethylene‐glycol‐functionalized molybdenum disulfide (PEG‐MoS₂) nanoflowers with azo initiator and phase‐change material (PCM). Under near‐infrared laser (NIR) irradiation, the photothermal feature of PEG‐MoS₂ induces the decomposition of AIBI to produce free radicals. Furthermore, PEG‐MoS₂ can facilitate GSH oxidation without releasing toxic metal ions, greatly promoting tumor apoptosis and avoiding the introduction of toxic metal ions. This is the first example of the use of intelligent MoS₂‐based nanoflowers as a benign GSH scavenger for enhanced cancer treatment.     

Tuning the Amphiphilicity of Building Blocks: Controlled Self‐Assembly and Disassembly for Functional Supramolecular Materials

Amphiphilicity is one of the molecular bases for self‐assembly. By tuning the amphiphilicity of building blocks, controllable self‐assembly can be realized. This article reviews different routes for tuning amphiphilicity and discusses different possibilities for self‐assembly and disassembly in a controlled manner. In general, this includes irreversible and reversible routes. The irreversible routes concern irreversible reactions taking place on the building blocks and changing their molecular amphiphilicity. The building blocks are then able to self‐assemble to form different supramolecular structures, but cannot remain stable upon loss of amphiphilicity. Compared to the irreversible routes, the reversible routes are more attractive due to the good control over the assembly and disassembly of the supramolecular structure formed via tuning of the amphiphilicity. These routes involve reversible chemical reactions and supramolecular approaches, and different external stimuli can be used to trigger reversible changes of amphiphilicity, including light, redox, pH, and enzymes. It is anticipated that this line of research can lead to the fabrication of new functional supramolecular assemblies and materials.     

Immobilization of ALA‐ZnII Coordination Polymer Pro‐photosensitizers on Magnetite Colloidal Supraparticles for Target Photodynamic Therapy of Bladder Cancer

5‐Aminolevulinic acid (ALA) is a widely used photodynamic therapy (PDT) prodrug in the clinic. It can be metalized to the photosensitizer PpIX, which produces toxic singlet oxygen to kill cancer cells upon visible light irradiation. Herein, a core/shell‐structured vehicle is designed to comprise magnetite colloidal supraparticles (MCSPs) as cores and ALA‐Zn^II coordination polymers as shells (Fe₃O₄@ALA‐Zn^II) for target pro‐photosensitizer delivery. The coordination polymers with 2D layered structures are locally deposited on the MCSPs by the complexation of the ALA and Zn^II ions, and are readily controlled by varying the feed precursors and reaction temperatures. The maximum conjugated ALA amount is up to 17%. The Fe₃O₄@ALA‐Zn^II microspheres exhibit pH‐sensitive release of ALA in acidic environment and rapid magnetic responsiveness. Cytotoxicity results demonstrate that Fe₃O₄@ALA‐Zn^II shows a significant inhibitory effect to T24 cells and is nontoxic to 293T normal cells as exposed to the 630 nm visible light for a very short time, which may due to the selective accumulation of ALA‐induced PpIX in T24 cancer cells. Compared to the ALA used alone, the coordination polymer form is more efficient because of the bioactivity of incorporated Zn ions despite underlying the same apoptosis mechanism as ALA agent.     

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.     

Redox‐Triggered Gatekeeper‐Enveloped Starlike Hollow Silica Nanoparticles for Intelligent Delivery Systems

The design and development of multifunctional carriers for drug delivery based on hollow nanoparticles (HNPs) have attracted intense interests. Ordinary spherical HNPs are demonstrated to be promising candidates. However, the application of HNPs with special morphologies has rarely been reported. HNPs with sharp horns are expected to own higher endocytosis efficiencies than spherical counterparts. In this work, novel starlike hollow silica nanoparticles (SHNPs) with different sizes are proposed as platforms for the fabrication of redox‐triggered multifunctional systems for synergy of gene therapy and chemotherapy. The CD‐PGEA gene vectors (consisting of β‐CD cores and ethanolamine‐functionalized poly(glycidyl methacrylate) (denoted BUCT‐PGEA) arms) are introduced ingeniously onto the surfaces of SHNPs with plentiful disulfide bond‐linked adamantine guests. The resulting supramolecular assemblies (SHNP‐PGEAs) possess redox‐responsive gatekeepers for loaded drugs in the cavities of SHNPs. Meanwhile, they also demonstrate excellent performances to deliver genes. The gene transfection efficiencies, controlled drug release behaviors, and synergistic antitumor effect of hollow silica‐based carriers with different morphologies are investigated in detail. Compared with ordinary spherical HNP‐based counterparts, SHNP‐PGEA carriers with six sharp horns are proven to be superior gene vectors and possess better efficacy for cellular uptake and antitumor effects. The present multifunctional carriers based on SHNPs will have promising applications in drug/gene codelivery and cancer treatment.     

Cucurbit[8]uril‐Regulated Colloidal Dispersions Exhibiting Photocontrolled Rheological Behavior

In situ photocontrol over shear‐thickening of condensed colloidal dispersions is of paramount importance in a wide range of applications including process technology and photorheological fluids. Its development and practicability, however, are hampered by the lack of well‐designed photoresponsive systems. Here, a colloidal suspension whose rheological behavior is readily switchable between shear‐thinning and shear‐thickening using an external light stimulus is reported. This smart colloidal solution contains hybrid raspberry‐like colloids prepared by employing cucurbit[8]uril as a supramolecular linker to assemble functional Fe₃O₄ nanoparticles onto a silica core. The formed raspberry colloids are photoresponsive and can be reversibly disassembled under UV irradiation.     

Near‐Infrared Switchable Fullerene‐Based Synergy Therapy for Alzheimer's Disease

C₆₀ has a special dual function; it can act as both a powerful reactive oxygen species (ROS) producer under UV or visible light and an ROS scavenger in the dark. However, ROS has double‐edged effects in living systems. It is still a great challenge for biomedical application to switch and adjust the two opposite properties of C₆₀ in one system. Herein, UCNP@C₆₀‐pep (UCNP: upconversion nanoparticle, pep: Aβ‐target peptide KLVFF) is designed as a near‐infrared‐switchable nanoplatform for synergy therapy of Alzheimer's disease (AD). Under near‐infrared (NIR) light, the Aβ‐targeting hybrid nanoparticles produce ROS and result in Aβ photooxygenation, which can hinder Aβ aggregation and mitigate the attendant cytotoxicity. In the dark, UCNP@C₆₀‐pep shows protective effects against the increased oxidative stress. The ROS‐generating and ROS‐quenching abilities of UCNP@C₆₀‐pep are both beneficial for decreasing Aβ‐induced neurotoxicity and extending the longevity of the commonly used transgenic AD model Caenorhabditis elegans CL2006. Moreover, UCNP@C60‐pep can also be used for upconversion luminescence (UCL) and magnetic resonance imaging (MRI), which has benefits for “image‐guided therapy.” This study may offer a new perspective for the biological applications of C₆₀.