Tetraphenylethylene‐Interweaving Conjugated Macrocycle Polymer Materials as Two‐Photon Fluorescence Sensors for Metal Ions and Organic Molecules

A luminescent conjugated macrocycle polymer (CMP) with strong two‐photon fluorescence property, namely, P[5]‐TPE‐CMP, is constructed from ditriflate‐functionalized pillar[5]arene and a 1,1,2,2‐tetrakis(4‐ethynylphenyl)ethylene (TPE) linker through a Sonogashira–Hagihara cross‐coupling reaction. Significantly, in sharp contrast with the corresponding conjugated microporous polymer without synthetic macrocycles, P[5]‐TPE‐CMP shows an outstanding stability against photobleaching and exhibits highly selective cation sensing capability toward Fe³⁺ at different excitation wavelengths (both UV and red–near‐infrared regions). Meanwhile, its fluorescence could also be sufficiently quenched by 4‐amino azobenzene, a frequently used organic dye that is certified to be carcinogenic, as compared with a group of common organic compounds. This work paves a new way for enhancing the properties of porous organic polymers through the introduction of supramolecular macrocycles like macrocyclic arenes.     

Efficient Aggregation‐Induced Emission Manipulated by Polymer Host Materials

Linear copolymer hosts bearing a number of pillar[5]arene dangling side chains are synthesized for the facile construction of highly emissive supramolecular polymer networks (SPNs) upon noncovalently cross‐linking with a series of tetraphenyethylene (TPE)‐based tetratopic guests terminated with different functional groups through supramolecular host–guest interactions. An extremely high fluorescence quantum yield (98.22%) of the SPNs materials is obtained in tetrahydrofuran (THF) by fine‐tuning the parameters, and meanwhile supramolecular light‐harvesting systems based on spherical supramolecular nanoparticles are constructed by interweaving 9,10‐distyrylanthracene (DSA) and TPE‐based guest molecules of aggregation‐induced emission (AIE) with the copolymer hosts in the mixed solvent of THF/H₂O. The present study not only illustrates the restriction of the intramolecular rotations (RIR)‐ruled emission enhancement mechanism regulated particularly by macrocyclic arene‐containing copolymer hosts, but also suggests a new self‐assembly approach to construct high‐performance light‐harvesting materials.     

Light‐Powered Directional Nanofluidic Ion Transport in Kirigami‐Made Asymmetric Photonic‐Ionic Devices

Nacre‐mimetic 2D nanofluidic materials with densely packed sub‐nanometer‐height lamellar channels find widespread applications in water‐, energy‐, and environment‐related aspects by virtue of their scalable fabrication methods and exceptional transport properties. Recently, light‐powered nanofluidic ion transport in synthetic materials gained considerable attention for its remote, noninvasive, and active control of the membrane transport property using the energy of light. Toward practical application, a critical challenge is to overcome the dependence on inhomogeneous or site‐specific light illumination. Here, asymmetric photonic‐ionic devices based on kirigami‐tailored graphene oxide paper are fabricated, and directional nanofluidic ion transport properties therein powered by full‐area light illumination are demonstrated. The in‐plane asymmetry of the graphene oxide paper is essential to the generation of photoelectric driving force under homogeneous illumination. This light‐powered ion transport phenomenon is explained based on a modified carrier diffusion model. In asymmetric nanofluidic structures, enhanced recombination of photoexcited charge carriers at the membrane boundary breaks the electric potential balance in the horizontal direction, and thus drives the ion transport in that direction under symmetric illumination. The kirigami‐based strategy provides a facile and scalable way to fabricate paper‐like photonic‐ionic devices with arbitrary shapes, working as fundamental elements for large‐scale light‐harvesting nanofluidic circuits.     

Microfluidics: Accelerated Biofluid Filling in Complex Microfluidic Networks by Vacuum‐Pressure Accelerated Movement (V‐PAM) (Small 33/2016)

Rapid fluid transport and exchange are critical operations involved in many microfluidic applications. However, conventional mechanisms used for driving fluid transport in microfluidics, such as micropumping and high pressure, can be inaccurate and difficult for implementation for integrated microfluidics containing control components and closed compartments. Here, a technology has been developed termed Vacuum–Pressure Accelerated Movement (V‐PAM) capable of significantly enhancing biofluid transport in complex microfluidic environments containing dead‐end channels and closed chambers. Operation of the V‐PAM entails a pressurized fluid loading into microfluidic channels where gas confined inside can rapidly be dissipated through permeation through a thin, gas‐permeable membrane sandwiched between microfluidic channels and a network of vacuum channels. Effects of different structural and operational parameters of the V‐PAM for promoting fluid filling in microfluidic environments have been studied systematically. This work further demonstrates the applicability of V‐PAM for rapid filling of temperature‐sensitive hydrogels and unprocessed whole blood into complex irregular microfluidic networks such as microfluidic leaf venation patterns and blood circulatory systems. Together, the V‐PAM technology provides a promising generic microfluidic tool for advanced fluid control and transport in integrated microfluidics for different microfluidic diagnosis, organs‐on‐chips, and biomimetic studies.     

Metallicity‐Dependent Ultrafast Water Transport in Carbon Nanotubes

Carbon nanotubes (CNTs) with hydrophobic and atomically smooth inner channels are promising for building ultrahigh‐flux nanofluidic platforms for energy harvesting, health monitoring, and water purification. Conventional wisdom is that nanoconfinement effects determine water transport in CNTs. Here, using full‐atomistic molecular dynamics simulations, it is shown that water transport behavior in CNTs strongly correlates with the electronic properties of single‐walled CNTs (metallic (met) vs semiconducting (s/c)), which is as dominant as the effect of nanoconfinement. Three pairs of CNTs (i.e., (8,8)_met, 10.85 Å vs (9,7)_s/c, 10.88 Å; (9,8)_s/c, 11.53 Å vs (10,7)_met, 11.59 Å; and (9,9)_met, 12.20 Å vs (10,8)_s/c, 12.23 Å) are used to investigate the roles of diameter and metallicity. Specifically, the (9,8)_s/c can restrict the hydrogen‐bonding‐mediated structuring of water and give the highest reduction in carbon–water interaction energy, providing an extraordinarily high water flux, around 250 times that of the commercial reverse osmosis membranes and approximately fourfold higher than the flux of the state‐of‐the‐art boron nitrate nanotubes. Further, the high performance of (9,8)_s/c is also reproducible when embedded in lipid bilayers as synthetic high‐water flux porins. Given the increasing availability of high‐purity CNTs, these findings provide valuable guides for realizing novel CNT‐enhanced nanofluidic systems.     

Contribution of aquaporins to cellular water transport observed by a microfluidic cell volume sensor

Here we demonstrate that an impedance-based microfluidic cell volume sensor can be used to study the roles of aquaporin (AQP) in cellular water permeability and screen AQP-specific drugs. Human embryonic kidney (HEK-293) cells were transiently transfected with AQP3- or AQP4-encoding genes to express AQPs in plasma membranes. The swelling of cells in response to hypotonic stimulation was traced in real time using the sensor. Two time constants were obtained by fitting the swelling curves with a two-exponential function, a fast time constant associated with osmotic water permeability of AQP-expressing cells and a slow phase time constant associated mainly with water diffusion through lipid bilayers in the nontransfected cells. The AQP-expressing cells showed at least 10x faster osmotic water transport than control cells. Using the volume sensor, we examined the effects of Hg (2+) and Ni (2+) on the water transport via AQPs. Hg (2+) inhibited the water flux in AQP3-expressing cells irreversibly, while Ni (2+) blocked the AQP3 channels reversibly. Neither of the two ions blocked the AQP4 channels. The microfluidic volume sensor can sense changes in cell volume in real time, which enables perfusion of various reagents sequentially. It provides a convenient tool for studying the effect of reagents on the function and regulation mechanism of AQPs.     

Dual‐Layer Superamphiphobic/Superhydrophobic‐Oleophilic Nanofibrous Membranes with Unidirectional Oil‐Transport Ability and Strengthened Oil–Water Separation Performance

Thin porous membranes with unidirectional oil‐transport capacity offer great opportunities for intelligent manipulation of oil fluids and development of advanced membrane technologies. However, directional oil‐transport membranes and their unique membrane properties have seldom been reported in research literature. Here, it is proven that a dual‐layer nanofibrous membrane comprising a layer of superamphiphobic nanofibers and a layer of superhydrophobic oleophilic nanofibers has an unexpected directional oil‐transport ability, but is highly superhydrophobic to liquid water. This novel fibrous membrane is prepared by a layered electrospinning technique using poly(vinylidene fluoride‐hexafluoropropylene) (PVDF‐HFP), PVDP‐HFP containing well‐dispersed FD‐POSS (fluorinated decyl polyhedral oligomeric silsesquioxanes), and FAS (fluorinated alkyl silane) as materials. The directional oil‐transport is selective only to oil fluids with a surface tension in the range of 23.8–34.0 mN m^–1. By using a mixture of diesel and water, it is further proven that this dual‐layer nanofibrous membrane has a higher diesel–water separation ability than the single‐layer nanofiber membranes. This novel nanofibrous membrane and the incredible oil‐transport ability may lead to the development of intelligent membrane materials and advanced oil–water separation technologies for diverse applications in daily life and industry.     

Light‐Triggered Biomimetic Nanoerythrocyte for Tumor‐Targeted Lung Metastatic Combination Therapy of Malignant Melanoma

Red blood cell (RBC) membrane‐cloaked nanoparticles, reserving the intact cell membrane structure and membrane protein, can gain excellent cell‐specific functions such as long blood circulation and immune escape, providing a promising therapy nanoplatform for drug delivery. Herein, a novel RBC membrane biomimetic combination therapeutic system with tumor targeting ability is constructed by embedding bovine serum albumin (BSA) encapsulated with 1,2‐diaminocyclohexane‐platinum (II) (DACHPt) and indocyanine green (ICG) in the targeting peptide‐modified erythrocyte membrane (R‐RBC@BPtI) for enhancing tumor internalization and synergetic chemophototherapy. R‐RBC@BPtI displays excellent stability and high encapsulation efficiency with multiple cores enveloped in the membrane. Benefited from the stealth functionality and targeting modification of erythrocyte membranes, R‐RBC@BPtI can significantly promote tumor targeting and cellular uptake. Under the near‐infrared laser stimuli, R‐RBC@BPtI presents remarkable instability by singlet oxygen and heat‐mediated cleavage so as to trigger effective drug release, thereby achieving deep penetration and accumulation of DACHPt and ROS in the tumor site. Consequently, R‐RBC@BPtI with tumor‐specific targeting ability accomplishes remarkable ablation of tumors and suppressed lung metastasis in vivo by photothermal and chemotherapy combined ablation under phototriggering. This research provides a novel strategy of targeted biomimetic nanoplatforms for combined cancer chemotherapy–phototherapy.     

Investigating Structural Alterations in Pyrogallol[4]arene‐Pyrene Nanotubular Frameworks

Small‐angle neutron scattering (SANS) and diffusion NMR studies are performed to investigate the stability and geometry of hydrogen‐bonded pyrene‐guest‐containing C‐hexylpyrogallol[4]arene (PgC₆‐pyrene) nanotubular frameworks in solution. In the solid state, hydrogen‐bonded pyrogallol[4]arene tubes are formed; however, the scattering data for PgC₆‐pyrene assemblies in acetone are best modeled as dimeric spheres of PgC₆ with no pyrene guest. The result of diffusion NMR study also indicates the rearrangement of tubular entity into spherical framework in acetone. This is the first example of structural transformation of pyrogallol[4]arene nanotubes (guest‐exo) in solution. Individual hydrogen‐bonded spheres of PgC₆ exhibits a uniform radius of ca. 8.6 Å and a diffusion coefficient of 9.12 × 10^?10 m² s^?1 in acetone. The diffusion NMR measurements further gave, for the first time, insights into how the type of solvent (acetone vs. methanol vs. acetontitrile/D₂O) governs the structural differences in these nanoassemblies. Solution‐phase structural alteration observed for PgC₆‐pyrene gives evidence of enhanced stability of pyrogallol[4]arene nanocapsules over nanotubes.     

Energy‐Efficient Oil–Water Separation of Biomimetic Copper Membrane with Multiscale Hierarchical Dendritic Structures

Membrane‐based materials with special surface wettability have been applied widely for the treatment of increasing industrial oily waste water, as well as frequent oil spill accidents. However, traditional technologies are energy‐intensive and limited, either by fouling or by the inability of a single membrane to separate all types of oil–water mixtures. Herein, a biomimetic monolayer copper membrane (BMCM), composed of multiscale hierarchical dendritic structures, is cleverly designed and successfully fabricated on steel mesh substrate. It not only possesses the ability of energy‐efficient oil–water separation but also excellent self‐recovery anti‐oil‐fouling properties (<150 s). The BMCM even keeps high separation efficiency (>93%) after ten‐time cycling tests. More importantly, it retains efficient oil–water separation capacity for five different oils. In fact, these advanced features are benefited by the synergistic effect of chemical compositions and physical structures, which is inspired by the typical nonwetting strategy of butterfly wing scales. The findings in this work may inspire a facile but effective strategy for repeatable and antipollution oil–water separation, which is more suitable for various applications under practical conditions, such as wastewater treatment, fuel purification, separation of commercially relevant oily water, and so forth.     

Calixarene-based photoresponsive ion carrier for the control of Na flux across a lipid bilayer membrane by visible light

A photoresponsive ion carrier based on calix[4]arene was synthesized for the control of Na⁺ flux across lipid bilayer membranes by visible light. Calix[4]arene was chosen as a basic skeleton of a photoresponsive ion carrier because its ether derivatives are known to act as Na⁺ ion carriers in lipid bilayer membranes. For the synthesis of a photoresponsive carrier, dimethylaminoazobenzene was introduced as a photochromic moiety to an ether derivative of p-tert-butylcalix[4]arene. The ion transport ability of the dimethylaminoazobenzene appended calix[4]arene was examined by using a voltage-clamp method. When the calix[4]arene derivative was incorporated into a planar lipid bilayer membrane which separated two chambers filled with 100 mM of NaCl solutions, membrane currents resulting from Na⁺ flux were observed under applying external voltages between two chambers. The concentration dependence of the calix[4]arene derivative on the membrane currents indicated the formation of a 1:1 complex with Na⁺ ions for the calix[4]arene-mediated ion transport across the lipid bilayer membrane. By using visible light (> 400 nm), Na⁺ flux across lipid bilayer membranes containing the dimethylaminoazobenzene appended calix[4]arene derivative could be controlled.     

Engineering Biomimetic Platesomes for pH‐Responsive Drug Delivery and Enhanced Antitumor Activity

Biomimetic camouflage, i.e., using natural cell membranes for drug delivery, has demonstrated advantages over synthetic materials in both pharmacokinetics and biocompatibility, and so represents a promising solution for the development of safe nanomedicine. However, only limited efforts have been dedicated to engineering such camouflage to endow it with optimized or additional properties, in particular properties critical to a “smart” drug delivery system, such as stimuli‐responsive drug release. A pH‐responsive biomimetic “platesome” for specific drug delivery to tumors and tumor‐triggered drug release is described. This platesome nanovehicle is constructed by merging platelet membranes with functionalized synthetic liposomes and exhibits enhanced tumor affinity, due to its platelet membrane–based camouflage, and selectively releases its cargo in response to the acidic microenvironment of lysosomal compartments. In mouse cancer models, it shows significantly better antitumor efficacy than nanoformulations based on a platesome without pH responsiveness or those based on traditional pH‐sensitive liposomes. A convenient way to incorporate stimuli‐responsive features into biomimetic nanoparticles is described, demonstrating the potential of engineered cell membranes as biomimetic camouflages for a new generation of biocompatible and efficient nanocarriers.     

Biomolecule‐Functionalized Solid‐State Ion Nanochannels/Nanopores: Features and Techniques

Solid‐state ion nanochannels/nanopores, the biomimetic products of biological ion channels, are promising materials in real‐world applications due to their robust mechanical and controllable chemical properties. Functionalizations of solid‐state ion nanochannels/nanopores by biomolecules pave a wide way for the introduction of varied properties from biomolecules to solid‐state ion nanochannels/nanopores, making them smart in response to analytes or external stimuli and regulating the transport of ions/molecules. In this review, two features for nanochannels/nanopores functionalized by biomolecules are abstracted, i.e., specificity and signal amplification. Both of the two features are demonstrated from three kinds of nanochannels/nanopores: nucleic acid–functionalized nanochannels/nanopores, protein‐functionalized nanochannels/nanopores, and small biomolecule‐functionalized nanochannels/nanopores, respectively. Meanwhile, the fundamental mechanisms of these combinations between biomolecules and nanochannels/nanopores are explored, providing reasonable constructs for applications in sensing, transport, and energy conversion. And then, the techniques of functionalizations and the basic principle about biomolecules onto the solid‐state ion nanochannels/nanopores are summarized. Finally, some views about the future developments of the biomolecule‐functionalized nanochannels/nanopores are proposed.     

Genetically Engineered Liposome‐like Nanovesicles as Active Targeted Transport Platform

Ligand‐targeted delivery of drug molecules to various types of tumor cells remains a major challenge in precision medicine. Inspired by the secretion process and natural cargo delivery functions of natural exosomes, biomimetic synthetic strategies are exploited to prepare biofunctionalized liposome‐like nanovesicles (BLNs) that can artificially display a wide variety of targeting protein/peptide ligands and directly encapsulate medical agents for enhanced drug delivery. Here, as a proof of concept, genetically engineered BLNs, which display human epidermal growth factor (hEGF) or anti‐HER2 Affibody as targeting moieties, are developed to, respectively, target two types of tumor cells. Notably, in comparison to synthetic liposomes covalently coupled with hEGF, it is demonstrated in this work that biosynthetically displayed hEGF ligands on BLNs possess higher biological activities and targeting capabilities. Additionally, treatments with doxorubicin‐loaded BLNs displaying Affibody ligands exhibit much better antitumor therapeutic outcomes than clinically approved liposomal doxorubicin (Doxil) in HER2‐overexpressing BT474 tumor xenograft models. These data suggest that BLN is suitable as a potent surrogate for conventional proteoliposomes or immunoliposomes as a result of excellent targeting capacities and facile production of BLNs.     

Tree‐Inspired Design for High‐Efficiency Water Extraction

The solar steam process, akin to the natural water cycle, is considered to be an attractive approach to address water scarcity issues globally. However, water extraction from groundwater, for example, has not been demonstrated using these existing technologies. Additionally, there are major unaddressed challenges in extracting potable water from seawater including salt accumulation and long‐term evaporation stability, which warrant further investigation. Herein, a high‐performance solar steam device composed entirely of natural wood is reported. The pristine, natural wood is cut along the transverse direction and the top surface is carbonized to create a unique bilayer structure. This tree‐inspired design offers distinct advantages for water extraction, including rapid water transport and evaporation in the mesoporous wood, high light absorption (≈99%) within the surface carbonized open wood channels, a low thermal conductivity to avoid thermal loss, and cost effectiveness. The device also exhibits long‐term stability in seawater without salt accumulation as well as high performance for underground water extraction. The tree‐inspired design offers an inexpensive and scalable solar energy harvesting and steam generation technology that can provide clean water globally, especially for rural or remote areas where water is not only scarce but also limited by water extraction materials and methods.     

Facilitated Water Transport through Graphene Oxide Membranes Functionalized with Aquaporin‐Mimicking Peptides

Water purification by membranes is widely investigated to address concerns related to the scarcity of clean water. Achieving high flux and rejection simultaneously is a difficult challenge using such membranes because these properties are mutually exclusive in common artificial membranes. Nature has developed a method for this task involving water‐channel membrane proteins known as aquaporins. Here, the design and fabrication of graphene oxide (GO)‐based membranes with a surface‐tethered peptide motif designed to mimic the water‐selective filter of natural aquaporins is reported. The short RF8 (RFRFRFRF, where R and F represent arginine and phenylalanine, respectively) octapeptide is a concentrated form of the core component of the Ar/R (aromatic/arginine) water‐selective filter in aquaporin. The resulting GO‐RF8 shows superior flux and high rejection similar to natural aquaporins. Molecular dynamics simulation reveal the unique configuration of RF8 peptides and the transport of water in GO‐RF8 membranes, supporting that RF8 effectively emulates the core function of aquaporins.     

Water‐Rich Biomimetic Composites with Abiotic Self‐Organizing Nanofiber Network

Load‐bearing soft tissues, e.g., cartilage, ligaments, and blood vessels, are made predominantly from water (65–90%) which is essential for nutrient transport to cells. Yet, they display amazing stiffness, toughness, strength, and deformability attributed to the reconfigurable 3D network from stiff collagen nanofibers and flexible proteoglycans. Existing hydrogels and composites partially achieve some of the mechanical properties of natural soft tissues, but at the expense of water content. Concurrently, water‐rich biomedical polymers are elastic but weak. Here, biomimetic composites from aramid nanofibers interlaced with poly(vinyl alcohol), with water contents of as high as 70–92%, are reported. With tensile moduli of ≈9.1 MPa, ultimate tensile strains of ≈325%, compressive strengths of ≈26 MPa, and fracture toughness of as high as ≈9200 J m^?2, their mechanical properties match or exceed those of prototype tissues, e.g., cartilage. Furthermore, with reconfigurable, noncovalent interactions at nanomaterial interfaces, the composite nanofiber network can adapt itself under stress, enabling abiotic soft tissue with multiscale self‐organization for effective load bearing and energy dissipation.     

Characterization of moulded‐fibre packaging with respect to water vapour sorption and permeation at different combinations of internal and external humidity

A moulded‐fibre packaging system was characterized under conditions simulating real‐life packaging of food. A steady‐state moisture flux through the moulded‐fibre packaging was generated by subjecting the system to different combinations of internal humidity [33–97% r.h. (0.33–0.97a_w of contents), RH(i)] and surrounding humidity [33–97% r.h., RH(e)]. The objective was to resolve whether a hygroscopic fibre material absorbs moisture proportional to the rate of moisture transport, and the moulded‐fibre material was thus characterized with respect to accumulation of moisture in the fibre material, water vapour transmission rate (WVTR) and permeability (k/x). These steady‐state properties showed significant asymmetry depending on direction of moisture transport. When moisture was transported out of the system [RH(i) > RH(e)] the fibre material adsorbed moisture to a considerable lesser extent compared to when moisture was transported into the system [RH(i) < RH(e)], just as (k/x) increased by 15–20%. Taking both directions of moisture transport into account, the moisture content of the fibre material depended largely on surrounding humidity, even at high internal humidity. Moisture contents ranged from 5.5 g/100 g dry fibre at RH(e) 33% r.h. to 16.4–25.1 g/100 g dry fibre at RH(e) 97% r.h. The observed asymmetry was shown to derive from the experimental set‐up and not from the material itself. A minimal theory based on the various transport steps in the experimental set‐up was proposed in order to qualitatively explain this asymmetry. The rate of moisture adsorption in moulded‐fibre was described by the normalized response function H(t). Response times to reach equilibrium moisture contents were 6 and 8 h for RH(e) 33 and 53% r.h., and 40 and 41 h for RH(e) 75 and 97% r.h. Copyright © 2004 John Wiley & Sons, Ltd.     

Perforated Bicontinuous Cubic Phases with pH‐Responsive Topological Channel Interconnectivity

Lipidic lyotropic liquid crystals are at the frontline of current research for release of target therapeutic molecules due to their unique structural complexity and the possibility of engineering stimuli‐triggered release of both hydrophilic and hydrophobic molecules. One of the most suitable lipidic mesophases for the encapsulation and delivery of drugs is the reversed double diamond bicontinuous cubic phase, in which two distinct and parallel networks of ～4 nm water channels percolate independently through the lipid bilayers, following a Pn3m space group symmetry. In the unperturbed Pn3m structure, the two sets of channels act as autonomous and non‐communicating 3D transport pathways. Here, a novel type of bicontinuous cubic phase is introduced, where the presence of OmpF membrane proteins at the bilayers provides unique topological interconnectivities among the two distinct sets of water channels, enabling molecular active gating among them. By a combination of small‐angle X‐ray scattering, release and ion conductivity experiments, it is shown that, without altering the Pn3m space group symmetry or the water channel diameter, the newly designed perforated bicontinuous cubic phase attains transport properties well beyond those of the standard mesophase, allowing faster, sustained release of bioactive target molecules. By further exploiting the pH‐mediated pore‐closing response mechanism of the double amino acid half‐ring architecture in the membrane protein, the pores of the perforated mesophase can be opened and closed with a pH trigger, enabling a fine modulation of the transport properties by only moderate changes in pH, which could open unexplored opportunities in the targeted delivery of bioactive compounds.     

Concurrent Drug Unplugging and Permeabilization of Polyprodrug‐Gated Crosslinked Vesicles for Cancer Combination Chemotherapy

Combination chemotherapy with both hydrophobic and hydrophilic therapeutic drugs is clinically vital toward the treatment of persistent cancers. Though conventional liposomes and polymeric vesicles possessing hydrophobic bilayers and aqueous interiors can serve as codelivery nanocarriers, it remains a considerable challenge to achieve synchronized release of both types of drugs due to distinct encapsulation mechanisms; premature release of water‐soluble cargos from unstable liposomes and ruptured vesicles is also a major concern. Herein, the fabrication of physiologically stable polyprodrug‐gated crosslinked vesicles (GCVs) via the self‐assembly of camptothecin (CPT) polyprodrug amphiphiles and in situ bilayer crosslinking through traceless sol–gel reaction is reported. Polyprodrug‐GCVs possess high CPT loading (>30 wt%) and minimized leakage of encapsulated hydrophilic doxorubicin (DOX) hydrochloride due to the suppressed permeability of crosslinked membrane, exhibiting extended blood circulation (t _1/2 > 13 h) with caged cytotoxicity in physiological circulation. Upon cellular uptake by cancer cells, cytosolic reductive milieu‐triggered CPT unplugging from vesicle bilayers is demonstrated to generate hydrophilic mesh channels and make the membrane highly permeable. Concurrently, it will promote DOX corelease from hydrophilic lumen (≈36‐fold increase). The reduction‐activated combination chemotherapeutic potency based on polyprodrug‐GCVs is confirmed by both in vitro and in vivo explorations.