Bioinspired Nano‐Prodrug with Enhanced Tumor Targeting and Increased Therapeutic Efficiency

Nanotechnology‐based drug delivery has a great potential to revolutionize cancer treatment by enhancing anticancer drug efficacy and reducing drug toxicity. Here, a bioinspired nano‐prodrug (BiNp) assembled by an antineoplastic peptidic derivative (FA‐KLA‐Hy‐DOX), a folate acid (FA)‐incorporated proapoptotic peptide (KLAKLAK)₂ (KLA) to doxorubicin (DOX) via an acid‐labile hydrozone bond (Hy) is constructed. The hydrophobic antineoplastic agent DOX is efficiently shielded in the core of nano‐prodrug. With FA targeting moieties on the surface, the obtained BiNp shows significant tumor‐targeting ability and enhances the specific uptake of cancer cells. Upon the trigger by the intracellular acidic microenvironment of endosomes, the antineoplastic agent DOX is released on‐demand and promotes the apoptosis of cancer cells. Simultaneously, the liberated FA‐KLA can induce the dysfunction of mitochondria and evoke mitochondria‐dependent apoptosis. In vitro and in vivo results show that the nano‐prodrug BiNp with integrated programmed functions exhibits remarkable inhibition of tumor and achieves a maximized therapeutic efficiency with a minimized side effect.     

Light‐Induced ROS Generation and 2‐DG‐Activated Endoplasmic Reticulum Stress by Antitumor Nanosystems: An Effective Combination Therapy by Regulating the Tumor Microenvironment

A multimodal cancer therapeutic nanoplatform is reported. It demonstrates a promising approach to synergistically regulating the tumor microenvironment. The combination of intracellular reactive oxygen species (ROS) generated by irradiation of photosensitizer and endoplasmic reticulum (ER) stress induced by 2‐deoxy‐glucose (2‐DG) has a profound effect on necrotic or apoptotic cell death. Especially, targeting metabolic pathway by 2‐DG is a promising strategy to promote the effect of photodynamic therapy and chemotherapy. The nanoplatform can readily release its cargoes inside cancer cells and combines the advantages of ROS‐sensitive releasing chemotherapeutic drugs, upregulating apoptosis pathways under ER stress, light‐induced generation of cytotoxic ROS, achieving tumor accumulation, and in vivo fluorescence imaging capability. This work highlights the importance of considering multiple intracellular stresses as design parameters for nanoscale functional materials in cell biology, immune response, as well as medical treatments of cancer, Alzheimer's disease, etc.     

Efficacy Dependence of Photodynamic Therapy Mediated by Upconversion Nanoparticles: Subcellular Positioning and Irradiation Productivity

Singlet oxygen (¹O₂), as an important kind of reactive oxygen species (ROS) and main therapeutic agent in photodynamic therapy (PDT), only have a half‐life of 40 ns and an effective radius of 20 nm, which cause significant obstacles for improving PDT efficacy. In this work, novel upconversion nanoparticle (UCN)‐based nanoplatforms are developed with a minimized distance between UCNs and a photosensitizer, protoporphyrin IX (PpIX), and a controllable payload of PpIX, to enhance and control ROS production. The ability of the nanoplatform to target different subcellular organelles such as cell membrane and mitochondria is demonstrated via surface modification of the nanoplatform with different targeting ligands. The results show that the mitochondria‐targeting nanoplatforms result in significantly increased capability of both tumor cell killing and inhibition of tumor growth. Subcellular targeting of nanoparticles leads to the death of cancer cells in different manners. However, the efficiency of ROS generation almost have no influence on the tumor cell viability during the period of evaluation. These findings suggest that specific subcellular targeting of the nanoplatforms enhances the PDT efficacy more effectively than the increase of ROS production, and may shed light on future novel designs of effective and controllable PDT nanoplatforms.     

Visualizing Oxidative Cellular Stress Induced by Nanoparticles in the Subcytotoxic Range Using Fluorescence Lifetime Imaging

Nanoparticles hold a great promise in biomedical science. However, due to their unique physical and chemical properties they can lead to overproduction of intracellular reactive oxygen species (ROS). As an important mechanism of nanotoxicity, there is a great need for sensitive and high‐throughput adaptable single‐cell ROS detection methods. Here, fluorescence lifetime imaging microscopy (FLIM) is employed for single‐cell ROS detection (FLIM‐ROX) providing increased sensitivity and enabling high‐throughput analysis in fixed and live cells. FLIM‐ROX owes its sensitivity to the discrimination of autofluorescence from the unique fluorescence lifetime of the ROS reporter dye. The effect of subcytotoxic amounts of cationic gold nanoparticles in J774A.1 cells and primary human macrophages on ROS generation is investigated. FLIM‐ROX measures very low ROS levels upon gold nanoparticle exposure, which is undetectable by the conventional method. It is demonstrated that cellular morphology changes, elevated senescence, and DNA damage link the resulting low‐level oxidative stress to cellular adverse effects and thus nanotoxicity. Multiphoton FLIM‐ROX enables the quantification of spatial ROS distribution in vivo, which is shown for skin tissue as a target for nanoparticle exposure. Thus, this innovative method allows identifying of low‐level ROS in vitro and in vivo and, subsequently, promotes understanding of ROS‐associated nanotoxicity.     

Dual pH/ROS‐Responsive Nanoplatform with Deep Tumor Penetration and Self‐Amplified Drug Release for Enhancing Tumor Chemotherapeutic Efficacy

Poor deep tumor penetration and incomplete intracellular drug release remain challenges for antitumor nanomedicine application in clinical settings. Herein, a nanomedicine (RLPA‐NPs) is developed that can achieve prolonged blood circulation, deep tumor penetration, active‐targeting of cancer cells, endosome/lysosome escape, and intracellular selectivity self‐amplified drug release for effective drug delivery. The RLPA‐NPs are constructed by encapsulation of a pH‐sensitive polymer octadecylamine‐poly(aspartate‐1‐(3‐aminopropyl) imidazole) (OA‐P(Asp‐API)) and a ROS‐generation agent, β‐Lapachone (Lap), in micelles assembled by the tumor‐penetration peptide internalizing RGD (iRGD)‐modified ROS‐responsive paclitaxel (PTX)‐prodrug. iRGD could promote RLPA‐NPs penetration into deep tumor tissue, and specific targeting to cancer cells. After internalization by cancer cells through receptor‐mediated endocytosis, OA‐P(Asp‐API) can rapidly protonate in the endosome's acidic environment, resulting in RLPA‐NPs escape from the endosome through the “proton sponge effect”. At the same time, the RLPA‐NPs micelle disassembles, releasing Lap and PTX‐prodrug. Subsequently, the released Lap could generate ROS, consequently amplifying and accelerating PTX release to kill tumor cells. The in vitro and in vivo studies demonstrated that RLPA‐NPs can significantly improve the therapeutic effect compared to control groups. Therefore, RLPA‐NPs are a promising nanoplatform for overcoming multiple physiological and pathological barriers to enhance drug delivery.     

A Mussel‐Inspired Persistent ROS‐Scavenging,Electroactive, and Osteoinductive Scaffold Based on Electrochemical‐Driven In Situ Nanoassembly

Conductive polymers are promising for bone regeneration because they can regulate cell behavior through electrical stimulation; moreover, they are antioxidative agents that can be used to protect cells and tissues from damage originating from reactive oxygen species (ROS). However, conductive polymers lack affinity to cells and osteoinductivity, which limits their application in tissue engineering. Herein, an electroactive, cell affinitive, persistent ROS‐scavenging, and osteoinductive porous Ti scaffold is prepared by the on‐surface in situ assembly of a polypyrrole‐polydopamine‐hydroxyapatite (PPy‐PDA‐HA) film through a layer‐by‐layer pulse electrodeposition (LBL‐PED) method. During LBL‐PED, the PPy‐PDA nanoparticles (NPs) and HA NPs are in situ synthesized and uniformly coated on a porous scaffold from inside to outside. PDA is entangled with and doped into PPy to enhance the ROS scavenging rate of the scaffold and realize repeatable, efficient ROS scavenging over a long period of time. HA and electrical stimulation synergistically promote osteogenic cell differentiation on PPy‐PDA‐HA films. Ultimately, the PPy‐PDA‐HA porous scaffold provides excellent bone regeneration through the synergistic effects of electroactivity, cell affinity, and antioxidative activity of the PPy‐PDA NPs and the osteoinductivity of HA NPs. This study provides a new strategy for functionalizing porous scaffolds that show great promise as implants for tissue regeneration.     

Langmuir–Blodgett Nanowire Devices for In Situ Probing of Zinc‐Ion Batteries

In situ monitoring the evolution of electrode materials in micro/nano scale is crucial to understand the intrinsic mechanism of rechargeable batteries. Here a novel on‐chip Langmuir–Blodgett nanowire (LBNW) microdevice is designed based on aligned and assembled MnO₂ nanowire quasimonolayer films for directly probing Zn‐ion batteries (ZIBs) in real‐time. With an interdigital device configuration, a splendid Ohmic contact between MnO₂ LBNWs and pyrolytic carbon current collector is demonstrated here, enabling a small polarization voltage. In addition, this work reveals, for the first time, that the conductance of MnO₂ LBNWs monotonically increases/decreases when the ZIBs are charged/discharged. Multistep phase transition is mainly responsible for the mechanism of the ZIBs, as evidenced by combined high‐resolution transmission electron microscopy and in situ Raman spectroscopy. This work provides a new and adaptable platform for microchip‐based in situ simultaneous electrochemical and physical detection of batteries, which would promote the fundamental and practical research of nanowire electrode materials in energy storage applications.     

Mitochondria‐Targeting Magnetic Composite Nanoparticles for Enhanced Phototherapy of Cancer

Photothermal therapy (PTT) and photodynamic therapy (PDT) are promising cancer treatment modalities in current days while the high laser power density demand and low tumor accumulation are key obstacles that have greatly restricted their development. Here, magnetic composite nanoparticles for dual‐modal PTT and PDT which have realized enhanced cancer therapeutic effect by mitochondria‐targeting are reported. Integrating PTT agent and photosensitizer together, the composite nanoparticles are able to generate heat and reactive oxygen species (ROS) simultaneously upon near infrared (NIR) laser irradiation. After surface modification of targeting ligands, the composite nanoparticles can be selectively delivered to the mitochondria, which amplify the cancer cell apoptosis induced by hyperthermia and the cytotoxic ROS. In this way, better photo therapeutic effects and much higher cytotoxicity are achieved by utilizing the composite nanoparticles than that treated with the same nanoparticles missing mitochondrial targeting unit at a low laser power density. Guided by NIR fluorescence imaging and magnetic resonance imaging, then these results are confirmed in a humanized orthotropic lung cancer model. The composite nanoparticles demonstrate high tumor accumulation and excellent tumor regression with minimal side effect upon NIR laser exposure. Therefore, the mitochondria‐targeting composite nanoparticles are expected to be an effective phototherapeutic platform in oncotherapy.     

Interfacing Inorganic Nanowire Arrays and Living Cells for Cellular Function Analysis

Inorganic nanowires are among the most attractive functional materials, which have emerged in the past two decades. They have demonstrated applications in information technology and energy conversion, but their utility in biological or biomedical research remains relatively under‐explored. Although nanowire‐based sensors have been frequently reported for biomolecular detection, interfacing nanowire arrays and living mammalian cells for the direct analysis of cellular functions is a very recent endeavor. Cell‐penetrating nanowires enabled effective delivery of biomolecules, electrical and optical stimulation and recording of intracellular signals over a long period of time. Non‐penetrating, high‐density nanowire arrays display rich interactions between the nanostructured substrate and the micro/nanoscale features of cell surfaces. Such interactions enable efficient capture of rare cells including circulating tumor cells and trafficking leukocytes from complex biospecimens. It also serves as a platform for probing cell traction force and neuronal guidance. The most recent advances in the field that exploits nanowire arrays (both penetrating and non‐penetrating) to perform rapid analysis of cellular functions potentially for disease diagnosis and monitoring are reviewed.     

Clinically Approved Carbon Nanoparticles with Oral Administration for Intestinal Radioprotection via Protecting the Small Intestinal Crypt Stem Cells and Maintaining the Balance of Intestinal Flora

The exploration of an old drug for new biomedical applications has an absolute predominance in shortening the clinical conversion time of drugs for clinical application. In this work, carbon nanoparticles suspension injection (CNSI), the first clinically approved carbon nanoparticles in China, is explored as a new nano‐radioprotective agent for potent intestinal radioprotection. CNSI shows powerful radioprotective performance in the intestine under oral administration, including efficient free radical scavenging ability, good biosafety, high chemical stability, and relatively long retention time. For example, CNSI shows high reactive oxygen species (ROS) scavenging activities, which effectively alleviates the mitochondrial dysfunction and DNA double‐strand breaks to protect the cells against radiation‐induced damage. Most importantly, this efficient ROS scavenging ability greatly helps restrain the apoptosis of the small intestinal epithelial and crypt stem cells, which decreases the damage of the mechanical barrier and thus relieves radiation enteritis. Moreover, CNSI helps remove the free radicals in the intestinal microenvironment and thus maintain the balance of intestinal flora so as to mitigate the radiation enteritis. The finding suggests a new application of clinically approved carbon nanoparticles, which not only promotes the development of new intestinal radioprotector, but also has a great potential for clinical transformation.     

Fibroblasts Cultured on Nanowires Exhibit Low Motility,Impaired Cell Division,and DNA Damage

Nanowires are commonly used as tools for interfacing living cells, acting as biomolecule‐delivery vectors or electrodes. It is generally assumed that the small size of the nanowires ensures a minimal cellular perturbation, yet the effects of nanowires on cell migration and proliferation remain largely unknown. Fibroblast behaviour on vertical nanowire arrays is investigated, and it is shown that cell motility and proliferation rate are reduced on nanowires. Fibroblasts cultured on long nanowires exhibit failed cell division, DNA damage, increased ROS content and respiration. Using focused ion beam milling and scanning electron microscopy, highly curved but intact nuclear membranes are observed, showing no direct contact between the nanowires and the DNA. The nanowires possibly induce cellular stress and high respiration rates, which trigger the formation of ROS, which in turn results in DNA damage. These results are important guidelines to the design and interpretation of experiments involving nanowire‐based transfection and electrical characterization of living cells.     

Programmed Nanococktail for Intracellular Cascade Reaction Regulating Self‐Synergistic Tumor Targeting Therapy

In this work, a ZnO based nanococktail with programmed functions is designed and synthesized for self‐synergistic tumor targeting therapy. The nanococktail can actively target tumors via specific interaction of hyaluronic acid (HA) with CD44 receptors and respond to HAase‐rich tumor microenvironment to induce intracellular cascade reaction for controlled therapy. The exposed cell‐penetrating peptide (R8) potentiates the cellular uptake of therapeutic nanoparticles into targeted tumor cells. Then ZnO cocktail will readily degrade in acidic endo/lysosomes and induce the production of desired reactive oxygen species (ROS) in situ. The destructive ROS not only leads to serious cell damage but also triggers the on‐demand drug release for precise chemotherapy, thus achieving enhanced antitumor efficiency synergistically. After tail vein injection of ZnO cocktail, a favorable tumor apoptosis rate (71.2 ± 8.2%) is detected, which is significantly superior to that of free drug, doxorubicin (12.9 ± 5.2%). Both in vitro and in vivo studies demonstrate that the tailor‐made ZnO cocktail with favorable biocompatibility, promising tumor specificity, and self‐synergistically therapeutic capacity opens new avenues for cancer therapy.     

Bioeffects of CdTe quantum dots on human umbilical vein endothelial cells

Quantum dots (QDs) hold great potential for applications in nanomedicine, however, their health effects are largely unknown. In the present study, the cytotoxicity and genotoxicity of CdTe QDs were examined in human umbilical vein endothelial cells (HUVECs). The QDs exhibited a dose-dependent inhibitory effect on cell growth. It was shown that after a 12 h treatment QDs at 1, 10, and 50 microg x ml(-1) induced formation of yH2AX foci, indicative of DNA damage, in a dose-dependent manner. Moreover, QD treatment clearly induced the generation of reactive oxygen species (ROS). Pre-treatment with N-acetyl-cysteine (NAC), a ROS scavenger, could inhibit the induction of ROS by QDs, as well as the formation of yH2AX foci. Taken together, our data indicate that CdTe QDs have cytotoxic and genotoxic effects on HUVECs, and that ROS generation may be involved in QD induced DNA damage.     

Self‐Destruction of Cancer Induced by Ag2S Amorphous Nanodots

Studies on distinctive performances and novel applications of amorphous inorganic nanomaterials are becoming attractive. Herein, Ag₂S amorphous and crystalline nanodots (ANDs and CNDs) are prepared via facile methods. In vitro and in vivo studies indicate that Ag₂S ANDs, rather than CNDs, can induce the self‐destruction of tumors, which can be attributed to their distinctive chemical properties, e.g., the higher electrochemical active surface area and lower redox potential well matching with the redox reaction requirement in the tumor microenvironment. Ag₂S ANDs can be oxidized by intracellular reactive oxygen species (ROS) to release Ag⁺, which further stimulates high generation of intracellular ROS. This mutual stimulation damages the mitochondria, induces apoptosis, and leads to the self‐destruction of the tumor. Moreover, Ag₂S ANDs do not show observable in vitro and in vivo side effects. These findings provide a promising self‐destructive strategy for cancer therapy by utilizing distinctive chemical properties of inorganic nanomaterials, while avoiding complicated external assistance.     

Highly Efficient Photosensitizers with Far‐Red/Near‐Infrared Aggregation‐Induced Emission for In Vitro and In Vivo Cancer Theranostics

Fluorescence‐imaging‐guided photodynamic therapy has emerged as a promising protocol for cancer theranostics. However, facile preparation of such a theranostic material for simultaneously achieving bright emission with long wavelength, high‐performance reactive oxygen species (ROS) generation, and good targeting‐specificity of cancer cells, is highly desirable but remains challenging. In this study, a novel type of far‐red/near‐infrared‐emissive fluorescent molecules with aggregation‐induced emission (AIE) characteristics is synthesized through a few steps reaction. These AIE luminogens (AIEgens) possess simple structures, excellent photostabilities, large Stokes shifts, bright emission, and good biocompatibilities. Meanwhile, their ROS generation is extremely efficient with up to 90.7% of ROS quantum yield, which is far superior to that of some popularly used photosensitizers. Importantly, these AIEgens are able to selectively target and ablate cancer cells over normal cells without the aid of any extra targeting ligands. Rather than using laser light, one of the presented AIEgens (MeTTPy) shows a remarkable tumor‐targeting photodynamic therapeutic effect by using an ultralow‐power lamp light (18 mW cm^?2). This study thus not only extends the applications scope of AIEgens, but also offers useful insights into designing a new generation of cancer theranostics.     

Synergistic Enzyme-Mimetic Catalysis-Based Non-Thermal Sonocavitation and Sonodynamic Therapy for Efficient Hypoxia Relief and Cancer Ablation (Small 42/2023)

Non-invasive cancer treatment strategies that enable local non-thermal ablation, hypoxia relief, and reactive oxygen species (ROS) production to achieve transiently destroying tumor tissue and long-term killing tumor cells would greatly facilitate their clinical applications. However, continuously generating oxygen cavitation nuclei, reducing the transient cavitation sound intensity threshold, relieving hypoxia, and improving its controllability in the ablation area still remains a significant challenge. Here, in this work, an Mn-coordinated polyphthalocyanine sonocavitation agent (Mn-SCA) with large d-π-conjugated network and atomic Mn-N sites is identified for the non-thermal sonocavitation and sonodynamic therapy in the liver cancer ablation. In the tumor microenvironment, the catalytical generation of oxygen assists cavitation formation and generates microjets to ablate liver cancer tissue and relieve hypoxia, this work reports for the first time to utilize the enzymatic properties of Mn-SCA to lower the cavitation threshold in situ. Moreover, under pHIFU irradiation, high reactive oxygen species (ROS) production can be achieved. The two merits in liver cancer ablation are demonstrated by cell destruction and high tumor inhibition efficiency. This work will help deepen the understanding of cavitation ablation and the sonodynamic mechanisms related to the nanostructures and guide the design of sonocavitation agents with high ROS production for solid tumor ablation.     

Cellular Deformations Induced by Conical Silicon Nanowire Arrays Facilitate Gene Delivery

Engineered cell–nanostructured interfaces generated by vertically aligned silicon nanowire (SiNW) arrays have become a promising platform for orchestrating cell behavior, function, and fate. However, the underlying mechanism in SiNW‐mediated intracellular access and delivery is still poorly understood. This study demonstrates the development of a gene delivery platform based on conical SiNW arrays for mechanical cell transfection, assisted by centrifugal force, for both adherent and nonadherent cells in vitro. Cells form focal adhesions on SiNWs within 6 h, and maintain high viability and motility. Such a functional and dynamic cell–SiNW interface features conformational changes in the plasma membrane and in some cases the nucleus, promoting both direct penetration and endocytosis; this synergistically facilitates SiNW‐mediated delivery of nucleic acids into immortalized cell lines, and into difficult‐to‐transfect primary immune T cells without pre‐activation. Moreover, transfected cells retrieved from SiNWs retain the capacity to proliferate—crucial to future biomedical applications. The results indicate that SiNW‐mediated intracellular delivery holds great promise for developing increasingly sophisticated investigative and therapeutic tools.     

Mitochondrion‐Anchoring Photosensitizer with Aggregation‐Induced Emission Characteristics Synergistically Boosts the Radiosensitivity of Cancer Cells to Ionizing Radiation

The first mitochondrion‐anchoring photosensitizer that specifically generates singlet oxygen (¹O₂) in mitochondria under white light irradiation that can serve as a highly effective radiosensitizer is reported here, significantly sensitizing cancer cells to ionizing radiation. An aggregation‐induced emission luminogen (AIEgen), namely DPA‐SCP, is rationally designed with α‐cyanostilbene as a simple building block to reveal AIE, diphenylamino (DPA) group as a strong electron donating group to benefit red emission and efficient light‐controlled ¹O₂ generation, as well as a pyridinium salt as the targeting moiety to ensure specific mitochondrial localization. The AIE signature endows DPA‐SCP with the capacity to visualize mitochondria in a fluorescence turn‐on mode. It is found that under optimized experimental condition, DPA‐SCP with white light does not lead to apoptosis/death of cancer cells, whereas provides an elevated ¹O₂ environment in the mitochondria. More importantly, increasing intracellular level of ¹O₂ originated from mitochondria is demonstrated to be a generic method to enhance the radiosensitivity of cancer cells with a supra‐additive synergistic effect of “0 + 1 > 1.” Noteworthy is that “DPA‐SCP + white light” achieves a high SER10 value of 1.62, which is much larger than that of the most popularly used radiosensitizers, gold nanoparticles (1.19), and paclitaxel (1.32).     

Activatable Semiconducting Theranostics: Simultaneous Generation and Ratiometric Photoacoustic Imaging of Reactive Oxygen Species In Vivo

Enhancing the generation of reactive oxygen species (ROS) is an effective anticancer strategy. However, it is a great challenge to control the production and to image ROS in vivo, both of which are vital for improving the efficacy and accuracy of cancer therapy. Herein, an activatable semiconducting theranostic nanoparticle (NP) platform is developed that can simultaneously enhance ROS generation while self‐monitoring its levels through ratiometric photoacoustic (PA) imaging. The NP platform can further guide in vivo therapeutic effect in tumors. The theranostic NP platform is composed of: (i) cisplatin prodrug and ferric ion catalyst for ROS generation, a part of combination cancer therapy; and (ii) a ratiometric PA imaging nanoprobe consisting of inert semiconducting perylene‐diimide (PDI) and ROS activatable near‐infrared dye (IR790s), used in ratiometric PA imaging of ROS during cancer treatment. Ratiometric PA signals are measured at two near‐infrared excitation wavelengths: 680 and 790 nm for PDI and IR790s, respectively. The measurements show highly accurate visualization of ^?OH generation in vivo. This novel ROS responsive organic theranostic NP allows not only synergistic cancer chemotherapy but also real‐time monitoring of the therapeutic effect through ratiometric PA imaging.     

Nanoconfinement‐Induced Giant Electrocaloric Effect in Ferroelectric Polymer Nanowire Array Integrated with Aluminum Oxide Membrane to Exhibit Record Cooling Power Density

The electrocaloric effect (ECE) offers a unique mechanism to realize environmentally friendly and highly efficient solid‐state cooling that completely differs from the conventional vapor‐compression refrigeration. Here a new class of hybrid films composed of ferroelectric polymer nanowire array and anodic aluminum oxide (AAO) membrane is reported, which displays pronounced ECE driven by relatively low electric fields. Under confinement and orientation of AAO channels on the crystallization of the polymer, the polymer nanowire array shows substantially enhanced ECE that is about three times that of the corresponding thin films. Simultaneously, the integrated AAO membrane forms thermally conducting channels for the polymer nanowires, enabling the efficient transfer of cooling energy and operation of the EC materials under high frequencies, which are unattainable based on the currently available EC structures. Consequently, the integrated polymer nanowire–AAO hybrid film exhibits the state‐of‐the‐art cooling power density, outperforming the current ferroelectric polymers, ceramics, and composites. This work opens a new route for the development of scalable, high‐performance EC materials for next‐generation refrigeration.