Photo‐ and pH‐Triggered Release of Anticancer Drugs from Mesoporous Silica‐Coated Pd@Ag Nanoparticles

A smart drug delivery system integrating both photothermal therapy and chemotherapy for killing cancer cells is reported. The delivery system is based on a mesoporous silica‐coated Pd@Ag nanoplates composite. The Pd@Ag nanoplate core can effectively absorb and convert near infrared (NIR) light into heat. The mesoporous silica shell is provided as the host for loading anticancer drug, doxorubicin (DOX). The mesoporous shell consists of large pores, ～10 nm in diameter, and allows the DOX loading as high as 49% in weight. DOX loaded core–shell nanoparticles exhibit a higher efficiency in killing cancer cells than free DOX. More importantly, DOX molecules are loaded in the mesopores shell through coordination bonds that are responsive to pH and heat. The release of DOX from the core‐shell delivery vehicles into cancer cells can be therefore triggered by the pH drop caused by endocytosis and also NIR irradiation. A synergistic effect of combining chemotherapy and photothermal therapy is observed in our core‐shell drug delivery system. The cell‐killing efficacy by DOX‐loaded core–shell particles under NIR irradiation is higher than the sum of chemotherapy by DOX‐loaded particles and photothermal therapy by core–shell particles without DOX.     

A Smart Nanoassembly for Multistage Targeted Drug Delivery and Magnetic Resonance Imaging

Efficient delivery of DNA‐toxin anticancer drugs into nucleus of targeted tumor cells while simultaneously minimizing the side effects to normal tissue is a major challenge for cancer therapy. Herein, a multistage continuous targeting strategy based on magnetic mesoporous silica nanoparticles to overcome the challenge is demonstrated. At the initial‐stage, the magnetic nanoparticle is capable of efficiently accumulating in tumor tissue guided by magnet. Following by the magnetic targeting, the targeting ligand gets it right into the cancer cell by receptor‐mediated endocytosis. Accompanied by endocytosis into the lysosomes, the nanoparticle reverses its surface charge from negative to positive which leads to the separation of charge‐conversional polymer from the nanoparticle to re‐expose the nuclear‐targeting TAT peptide. Finally, TAT peptide facilitates the carriers to enter nucleus and the DNA‐toxin camptothecin can inhibit topoisomerase I to induce cell apoptosis. Furthermore, the nano‐drug delivery system can be simultaneously used as predominant contrast agents for magnetic resonance imaging. This proof of concept might open the door to a new generation of carrier materials in the fields of targeted drug transport platform for cancer theranostics.     

Biocompatible,Uniform, and Redispersible Mesoporous Silica Nanoparticles for Cancer‐Targeted Drug Delivery In Vivo

Engineering multifunctional nanocarriers for targeted drug delivery shows promising potentials to revolutionize the cancer chemotherapy. Simple methods to optimize physicochemical characteristics and surface composition of the drug nanocarriers need to be developed in order to tackle major challenges for smooth translation of suitable nanocarriers to clinical applications. Here, rational development and utilization of multifunctional mesoporous silica nanoparticles (MSNPs) for targeting MDA‐MB‐231 xenograft model breast cancer in vivo are reported. Uniform and redispersible poly(ethylene glycol)‐incorporated MSNPs with three different sizes (48, 72, 100 nm) are synthesized. They are then functionalized with amino‐β‐cyclodextrin bridged by cleavable disulfide bonds, where amino‐β‐cyclodextrin blocks drugs inside the mesopores. The incorporation of active folate targeting ligand onto 48 nm of multifunctional MSNPs (PEG‐MSNPs48‐CD‐PEG‐FA) leads to improved and selective uptake of the nanoparticles into tumor. Targeted drug delivery capability of PEG‐MSNPs48‐CD‐PEG‐FA is demonstrated by significant inhibition of the tumor growth in mice treated with doxorubicin‐loaded nanoparticles, where doxorubicin is released triggered by intracellular acidic pH and glutathione. Doxorubicin‐loaded PEG‐MSNPs48‐CD‐PEG‐FA exhibits better in vivo therapeutic efficacy as compared with free doxorubicin and non‐targeted nanoparticles. Current study presents successful utilization of multifunctional MSNP‐based drug nanocarriers for targeted cancer therapy in vivo.     

Templated Assembly of pH‐Labile Polymer‐Drug Particles for Intracellular Drug Delivery

The preparation of pH‐labile polymer‐drug particles via mesoporous silica‐templated assembly for anticancer drug delivery into cancer cells is reported. The polymer‐drug conjugate is synthesized via thiol‐maleimide click chemistry using thiolated poly(methacrylic acid) (PMA_SH) and a pH‐labile doxorubicin (Dox) derivative. Drug‐loaded polymer particles that are stable under physiological conditions are obtained through infiltration of the conjugates into mesoporous silica particles, followed by cross‐linking the PMA_SH chains, and subsequent removal of the porous silica templates. The encapsulated Dox is released from the particles through cleavage of the hydrazone bonds between Dox and PMA_SH at endosomal/lysosomal pH. Cell viability assays show that the assembled PMA_SH particles have negligible cytotoxicity to LIM1899 human colorectal cancer cells. In comparison, Dox‐loaded PMA_SH particles cause significant cell death following internalization. The reported particles represent a novel and versatile class of stimuli‐responsive carriers for controlled drug delivery.     

Multifunctional Mesoporous Silica Nanoparticles for Cancer‐Targeted and Controlled Drug Delivery

Multifunctional mesoporous silica nanoparticles are developed in order to deliver anticancer drugs to specific cancer cells in a targeted and controlled manner. The nanoparticle surface is functionalized with amino‐β‐cyclodextrin rings bridged by cleavable disulfide bonds, blocking drugs inside the mesopores of the nanoparticles. Poly(ethylene glycol) polymers, functionalized with an adamantane unit at one end and a folate unit at the other end, are immobilized onto the nanoparticle surface through strong β‐cyclodextrin/adamantane complexation. The non‐cytotoxic nanoparticles containing the folate targeting units are efficiently trapped by folate‐receptor‐rich HeLa cancer cells through receptormmediated endocytosis, while folate‐receptor‐poor human embryonic kidney 293 normal cells show much lower endocytosis towards nanoparticles under the same conditions. The nanoparticles endocytosed by the cancer cells can release loaded doxorubicin into the cells triggered by acidic endosomal pH. After the nanoparticles escape from the endosome and enter into the cytoplasm of cancer cells, the high concentration of glutathione in the cytoplasm can lead to the removal of the β‐cyclodextrin capping rings by cleaving the pre‐installed disulfide bonds, further promoting the release of doxorubicin from the drug carriers. The high drug‐delivery efficacy of the multifunctional nanoparticles is attributed to the co‐operative effects of folate‐mediated targeting and stimuli‐triggered drug release. The present delivery system capable of delivering drugs in a targeted and controlled manner provides a novel platform for the next generation of therapeutics.     

Synthesis and Characterization of Positive‐Charge Functionalized Mesoporous Silica Nanoparticles for Oral Drug Delivery of an Anti‐Inflammatory Drug

We synthesized mesoporous silica nanoparticles (MSN) with different densities of surface positive charges. The positive surface charge was generated by incorporating trimethylammonium (TA) functional groups into the framework of MSN (MSN–TA) via direct co‐condensation of a TA‐silane and tetraethoxysilane (TEOS) in the presence of a base as a catalyst. These MSN–TA samples have well‐defined hexagonal structures with an average particle diameter of 100 nm, pore size of 2.7 nm, and surface area of about 1000 m² g^?1. Anionic drug molecules, Orange II (a fluorescent tracing molecule), and sulfasalazine (an anti‐inflammatory prodrug used for bowel disease), were effectively loaded into these MSN–TA samples and remained inside of the MSN–TA under acidic environment (pH 2–5). The amounts of loading of both Orange II and sulfasalazine were increased with increasing positive charge densities resulting from the increasing number of TA groups. When these drug‐loaded MSN–TA nanoparticles were placed in physiological buffer solution (pH 7.4), a partial negative surface charge on the MSN–TA was generated due to the deprotonation of silanol groups, and the strong electrostatic repulsion triggered a sustained release of the loaded molecules. MSN–TA as a nanovehicle for pH‐dependent loading and controllable release of anionic drug molecules can be used as an oral delivery drug systems targeting at intestine. These drugs can be remained trapped in the nanovehicle when passing through the stomach's acidic environment and be released in intestine where the environmental pH is close to neutral.     

Tumor Microenvironment‐Responsive Mesoporous MnO2‐Coated Upconversion Nanoplatform for Self‐Enhanced Tumor Theranostics

The insufficient blood flow and oxygen supply in solid tumor cause hypoxia, which leads to low sensitivity of tumorous cells and thus causing poor treatment outcome. Here, mesoporous manganese dioxide (mMnO₂) with ultrasensitive biodegradability in a tumor microenvironment (TME) is grown on upconversion photodynamic nanoparticles for not only TME‐enhanced bioimaging and drug release, but also for relieving tumor hypoxia, thereby markedly improving photodynamic therapy (PDT). In this nanoplatform, mesoporous silica coated upconversion nanoparticles (UCNPs@mSiO₂) with covalently loaded chlorin e6 are obtained as near‐infrared light mediated PDT agents, and then a mMnO₂ shell is grown via a facile ultrasonic way. Because of its unique mesoporous structure, the obtained nanoplatform postmodified with polyethylene glycol can load the chemotherapeutic drug of doxorubicin (DOX). When used for antitumor application, the mMnO₂ degrades rapidly within the TME, releasing Mn²⁺ ions, which couple with trimodal (upconversion luminescence, computed tomography (CT), and magnetic resonance imaging) imaging of UCNPs to perform a self‐enhanced imaging. Significantly, the degradation of mMnO₂ shell brings an efficient DOX release, and relieve tumor hypoxia by simultaneously inducing decomposition of tumor endogenous H₂O₂ and reduction of glutathione, thus achieving a highly potent chemo‐photodynamic therapy.     

Multifunctional Core/Shell Nanoparticles Self‐Assembled from pH‐Induced Thermosensitive Polymers for Targeted Intracellular Anticancer Drug Delivery

Core/shell nanoparticles that display a pH‐sensitive thermal response, self‐assembled from the amphiphilic tercopolymer, poly(N‐isopropylacrylamide‐co‐N,N‐dimethylacrylamide‐co‐10‐undecenoic acid) (P(NIPAAm‐co‐DMAAm‐co‐UA)), have recently been reported. In this study, folic acid is conjugated to the hydrophilic segment of the polymer through the free amine group (for targeting cancer cells that overexpress folate receptors) and cholesterol is grafted to the hydrophobic segment of the polymer. This polymer also self‐assembles into core/shell nanoparticles that exhibit pH‐induced temperature sensitivity, but they possess a more stable hydrophobic core than the original polymer P(NIPAAm‐co‐DMAAm‐co‐UA) and a shell containing folate molecules. An anticancer drug, doxorubicin (DOX), is encapsulated into the nanoparticles. DOX release is also pH‐dependent. DOX molecules delivered by P(NIPAAm‐co‐DMAAm‐co‐UA) and folate‐conjugated P(NIPAAm‐co‐DMAAm‐co‐UA)‐g‐cholesterol nanoparticles enter the nucleus more rapidly than those transported by P(NIPAAm‐co‐DMAAm)‐b‐poly(lactide‐co‐glycolide) nanoparticles, which are not pH sensitive. More importantly, these nanoparticles can recognize folate‐receptor‐expressing cancer cells. Compared to the nanoparticles without folate, the DOX‐loaded nanoparticles with folate yield a greater cellular uptake because of the folate‐receptor‐mediated endocytosis process, and, thus, higher cytotoxicity results. These multifunctional polymer core/shell nanoparticles may make a promising carrier to target drugs to cancer cells and release the drug molecules to the cytoplasm inside the cells.     

A Multi‐Gradient Targeting Drug Delivery System Based on RGD‐l‐TRAIL‐Labeled Magnetic Microbubbles for Cancer Theranostics

The accurately and efficiently targeted delivery of therapeutic/diagnostic agents into tumor areas in a controllable fashion remains a big challenge. Here, a novel cancer targeting magnetic microbubble is elaborately fabricated. First, the γ‐Fe₂O₃ magnetic iron oxide nanoparticles are optimized to chemically conjugate on the surface of polymer microbubbles. Then, arginine‐glycine‐aspartic acid‐l ‐tumor necrosis factor‐related apoptosis‐inducing ligand (RGD‐l ‐TRAIL), antitumor targeting fusion protein, is precisely conjugated with magnetic nanoparticles of microbubbles to construct RGD molecularly targeted magnetic microbubble, which is defined as RGD‐l ‐TRAIL@MMBs. Such RGD‐l ‐TRAIL@MMBs is endowed with the multigradient cascade targeting ability following by magnetic targeting, RGD, as well as enhanced permeability and retention effect regulated targeting to result in high cancerous tissue targeting efficiency. Due to the highly specific accumulation of RGD‐l ‐TRAIL@MMBs in the tumor, the accurate diagnostic information of tumor can be obtained by dual ultrasound and magnetic resonance imaging. After imaging, the TRAIL molecules as anticancer agent also get right into the cancer cells by nanoparticle‐ and RGD‐mediated endocytosis to effectively induce the tumor cell apoptosis. Therefore, RGD‐l ‐TRAIL conjugated magnetic microbubbles could be developed as a molecularly targeted multimodality imaging delivery system with the addition of chemotherapeutic cargoes to improve cancer diagnosis and therapy.     

A Triple‐Collaborative Strategy for High‐Performance Tumor Therapy by Multifunctional Mesoporous Silica‐Coated Gold Nanorods

To integrate treatments of photothermal therapy, photodynamic therapy (PDT), and chemotherapy, this study reports on a multifunctional nanocomposite based on mesoporous silica‐coated gold nanorod for high‐performance oncotherapy. Gold nanorod core is used as the hyperthermal agent and mesoporous silica shell is used as the reservoir of photosensitizer (Al(III) phthalocyanine chloride tetrasulfonic acid, AlPcS₄). The mesoporous silica shell is modified with β‐cyclodextrin (β‐CD) gatekeeper via redox‐cleavable Pt(IV) complex for controlled drug release. Furthermore, tumor targeting ligand (lactobionic acid, LA) and long‐circulating poly(ethylene glycol) chain are introduced via host–guest interaction. It is found that the nanocomposite can specifically target to hepatoma cells by virtue of the LA targeting moiety. Due to the abundant existence of reducing agents within tumor cells, β‐CD can be removed by reducing the Pt(IV) complex to active cisplatin drug for chemotherapy, along with the releasing of entrapped AlPcS₄ for effective PDT. As confirmed by in vitro and in vivo studies, the nanocomposite exhibits an obvious near‐infrared induced thermal effect, which significantly improves the PDT and chemotherapy efficiency, resulting in a superadditive therapeutic effect. This collaborative strategy paves the way toward high‐performance nanotherapeutics with a superior antitumor efficacy and much reduced side effects.     

Steric Protected and Illumination‐Activated Tumor Targeting Accessory for Endowing Drug‐Delivery Systems with Tumor Selectivity

Here, an ABA‐typed polymer, octadecyl‐polyethylene glycol (biotin)‐(o‐nitrobenzyl)‐octadecyl ester (CPB‐p‐C) with an o‐nitrobenzyl group inserted between polyethylene glycol (PEG) and octadecyl ester is synthesized as an illumination‐activated tumor targeting accessory for micelle‐based drug carriers. The functional accessory can form a flower‐like structure with folded PEG segments in aqueous solution to hide targeting biotin ligands in the core of the mixed micelle. Thus the specific binding between biotin and avidin can be suppressed by the steric hindrance of PEG shell. Upon illumination, the flower‐like structure of CPB‐p‐C is destroyed due to the cleavage of the o‐nitrobenzyl group and the biotin moieties are exposed on the surface of the micelle through the stretching process of PEG segments, generating ligand‐receptor‐mediated targeted delivery. By confocal laser scanning microscopy and flow cytometry, the illumination‐activated, tumor‐targeting delivery is studied. The influence of the amount of functional accessory in the mixed micelle on the targeting property is investigated and the optimal amount of CPB‐p‐C to achieve less side effects and better illumination activated tumor targeting activity is identified. The observed properties of CPB‐p‐C qualify it as a promising functional accessory to endow traditional drug‐delivery systems with tumor selectivity.     

Inorganic Drug‐Delivery Nanovehicle Conjugated with Cancer‐Cell‐Specific Ligand

The surface of layered double hydroxide nanoparticles, a potential drug‐delivery nanovehicle, is modified with the cancer‐cell‐specific ligand, folic acid. The surface modification is successfully accomplished through step‐by‐step coupling reactions with aminopropyltriethoxysilane and 1‐ethyl‐3‐(3‐dimethyl aminopropyl)‐carbodiimide. In order to evaluate the cancer‐cell targeting effect of folic‐acid‐grafted layered double hydroxide utilizing fluorescence‐related assay, both layered double hydroxide with and without folic acid moiety are labeled with fluorescein 5′‐isothiocyanate. The uptake of layered double hydroxide and folic acid conjugated into KB and A549 cells is visualized using fluorescence microscopy and measured by flow cytometry. Both chemical and biological assay results demonstrate that the folic acid molecules are indeed conjugated to the surface of layered double hydroxide and thus the selectivity of nanovehicles to cancer cells overexpressing folate receptors increases. In this study, it is suggested that layered double hydroxide nanoparticles can be used as drug‐delivery carriers with a targeting function due to the chemical conjugation with specific ligand.     

Gel–Liposome‐Mediated Co‐Delivery of Anticancer Membrane‐Associated Proteins and Small‐Molecule Drugs for Enhanced Therapeutic Efficacy

A programmed drug‐delivery system that can transport different anticancer therapeutics to their distinct targets holds vast promise for cancer treatment. Herein, a core–shell‐based “nanodepot” consisting of a liposomal core and a crosslinked‐gel shell (designated Gelipo) is developed for the sequential and site‐specific delivery (SSSD) of tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) and doxorubicin (Dox). As a small‐molecule drug intercalating the nuclear DNA, Dox is loaded in the aqueous core of the liposome, while TRAIL, acting on the death receptor (DR) on the plasma membrane, is encapsulated in the outer shell made of crosslinked hyaluronic acid (HA). The degradation of the HA shell by HAase that is concentrated in the tumor environment results in the rapid extracellular release of TRAIL and subsequent internalization of the liposomes. The parallel activity of TRAIL and Dox show synergistic anticancer efficacy. The half‐maximal inhibitory concentration (IC₅₀) of TRAIL and Dox co‐loaded Gelipo (TRAIL/Dox‐Gelipo) toward human breast cancer (MDA‐MB‐231) cells is 83 ng mL^–1 (Dox concentration), which presents a 5.9‐fold increase in the cytotoxicity compared to 569 ng mL^–1 of Dox‐loaded Gelipo (Dox‐Gelipo). Moreover, with the programmed choreography, Gelipo significantly improves the inhibition of the tumor growth in the MDA‐MB‐231 xenograft tumor animal model.     

Tumor‐Microenvironment‐Adaptive Nanoparticles Codeliver Paclitaxel and siRNA to Inhibit Growth and Lung Metastasis of Breast Cancer

Prolonged circulation, specific and effective uptake by tumor cells, and rapid intracellular drug release are three main factors for the drug delivery systems to win the battle against metastatic breast cancer. In this work, a tumor microenvironment‐adaptive nanoparticle co‐loading paclitaxel (PTX) and the anti‐metastasis siRNA targeting Twist is prepared. The nanoparticle consists of a pH‐sensitive core, a cationic shell, and a matrix metalloproteinase (MMP)‐cleavable polyethylene glycol (PEG) corona conjugated via a peptide linker. PEG will be cut away by MMPs at the tumor site, which endows the nanoparticle with smaller particle size and higher positive charge, leading to more efficient cellular uptake in tumor cells and higher intra‐tumor accumulation of both PTX and siRNA in the 4T1 tumor‐bearing mice models compared to the nanoparticles with irremovable PEG. In addition, acid‐triggered drug release in endo/lysosomes is achieved through the pH‐sensitive core. As a result, the MMP/pH dual‐sensitive nanoparticles significantly inhibit tumor growth and pulmonary metastasis. Therefore, this tumor‐microenvironment‐adaptive nanoparticle can be a promising codelivery vector for effective therapy of metastatic breast cancer due to simultaneously satisfying the requirements of long circulating time, efficient tumor cell targeting, and fast intracellular drug release.     

A Near‐Infrared Light‐Triggered Nanocarrier with Reversible DNA Valves for Intracellular Controlled Release

A near‐infrared (NIR) light‐triggered nanocarrier is developed for intracellular controlled release with good stability, high nuclease resistance, and good biocompatibility. The nanocarrier consists of a gold nanorod core and mesoporous silica shell, capped with reversible single‐stranded DNA valves, which are manipulated by switching between the laser on/off states. Upon laser irradiation, the valves of the nanocarrier open and the cargo molecules can be released from the mesopores. When the NIR laser is turned off, the valves close and the nanocarrier stops releasing the cargo molecules. The release amount of the cargo molecules can be controlled precisely by adjusting the irradiation time and the laser on‐off cycles. Confocal fluorescence imaging shows that the nanocarrier can be triggered by the laser irradiation and the controlled release can be accomplished in living cells. Moreover, the therapeutic effect toward cancer cells can also be regulated when the chemotherapeutic drug doxorubicin is loaded into the nanocarrier. This novel approach provides an ideal platform for drug delivery by a NIR light‐activated mechanism with precise control of area, time, and especially dosage.     

Real‐Time Imaging Tracking of Engineered Macrophages as Ultrasound‐Triggered Cell Bombs for Cancer Treatment

Cell‐based drug delivery systems are a promising platform for tumor‐targeted therapy due to their high drug‐loading capacities and inherent tumor‐homing abilities. However, the real‐time tracking of these carrier cells and controlled release of the encapsulated drugs are still challenging. Here, ultrasound‐activatable cell bombs are developed by encapsulating doxorubicin (DOX) and phase transformable perfluoropentane (PFP) into hollow mesoporous organosilica nanoparticles (HMONs) to prepare DOX/PFP‐loaded HMONs (DPH), followed by internalization into macrophages (RAW 264.7 cells). The resulting cell bombs (DPH‐RAWs) can maintain viability and actively home to the tumor. Especially, their migration can be tracked in real time using ultrasound due to the vaporization of a small portion of PFP during cell incubation at 37 °C. After accumulation at the tumor site, the further vaporization of remaining PFP can be triggered by a short‐pulsed high intensity focused ultrasound (HIFU) sonication, resulting in the generation of several large microbubbles, which destroys DPH‐RAWs and allows drug release out of these cells. The DPH‐RAWs combined with short‐pulsed HIFU sonication significantly inhibit tumor growth and prolong survival of tumor‐bearing mice. In conclusion, this study provides a new approach to cell‐based drug delivery systems for real‐time tracking of their migration and targeted cancer treatment.     

Self‐Assembled Nanoparticles with Dual Effects of Passive Tumor Targeting and Cancer‐Selective Anticancer Effects

Nanoparticular drug delivery systems may help to overcome the limitations of conventional chemotherapy. They have been reported to improve the specificity of distribution, the bioavailability, and the solubility of drugs, as well as the duration of drug efficacy, and helping to overcome multidrug resistance. Although various polymeric nanoparticles have been developed for delivery of anticancer agents, most nanoparticles still focus on solubilizing drugs, improving targeting ability, and reducing side effects. In particular, targeting to the tumor is typically improved through passive or active targeting. Despite great achievements in both strategies, yet to be resolved are issues of toxicity in normal cells and enhancement of tumor‐specificity. A new approach combining the dual strategies of passive tumor targeting and cancer‐selective efficacy is proposed. Recombinant human gelatin conjugated with lipoic acid (rHG‐LA) developed in this study forms nanoparticles spontaneously in aqueous solution and encapsulates alpha‐tocopheryl succinate (α‐TOS), a well‐known cancer‐selective apoptosis‐inducing agent, within a hydrophobic core during the self‐assembly. This study describes the promising applicability of α‐TOS‐loaded rHG‐LA nanoparticles with passive targeting ability and cancer‐specificity.     

Use of Ferritin Capped Mesoporous Silica Nanoparticles for Redox and pH Triggered Drug Release In Vitro and In Vivo

Mesoporous silica nanoparticles (MSNs) functionalized with redox‐sensitive or pH‐sensitive nanovalves for doxorubicin delivery and release by using recombinant human H chain ferritin (HFn) as a cap have been designed and fabricated. In both cases, transmission electron microscope observatory, dynamic light scattering change, Fourier transform infrared spectra examination, thermogravimetric analysis show that HFn can be chemically bonded to MSNs while retaining its ability to target transferrin receptor 1 (TfR1). Cargo loading and release studies demonstrate that HFn is an efficient capping agent, blocking the pores of MSN preventing cargo molecules from diffusing out, and is responsive to redox stimuli or pH changes. More importantly, HFn can not only cap the MSNs, but also enables targeted cargo delivery to malignant cells by binding to the TfR1 that has been overexpressed in various tumors, which can be reflected by the cell viability and fluorescence microscope analysis results comparing with cyclodextrin as the capping agent and TfR1 blocking assay. The in vivo study reveals the excellent efficacy of doxorubicin loaded and HFn capped MSNs on suppression of tumor growth. The new developed drug delivery system features mutually benefit and mutually support, providing strategy for achieving specific‐site therapeutics delivery systems.     

Tethered Lipid Bilayer Gates: Toward Extended Retention of Hydrophilic Cargo in Porous Nanocarriers

A high‐performance molecular gating system for efficient capping and delivery of hydrophilic cargo is reported. It integrates a mesoporous silica nanoparticle core and a lipid bilayer (LB) shell by covalent tethering via a hyperbranched polyethylenimine (PEI) cushion. When using calcein as a general model for hydrophilic drug molecules, a high payload is loaded into the porous structure due to greatly enhanced concentration of amino groups on the pore walls. Surprisingly, LB non‐disruptively resides on the porous surface in this system, despite the strong positive charge from PEI, originating from the covalent tethering of the inner leaflet, as well as preferential spanning over the pore openings facilitated by the stretching of PEI chains on the particle surface. An unprecedented high retention of negatively charged hydrophilic guest molecules after up to 1 week is consequently achieved, even in the presence of a membrane disrupting agent. Furthermore, a PEI‐induced charge conversion at neutral pH is conferred to the particles using a zwitterionic PC lipid as the outer leaflet of LB. Interestingly, the corresponding nanocarriers are able to promote cargo escape from endosomes. Subsequent delivery of the loaded hydrophilic cargo to the cytoplasm is observed despite the tight retention under extracellular conditions.     

Hollow Mesoporous Zirconia Nanocapsules for Drug Delivery

Hollow mesoporous zirconia nanocapsules (hm‐ZrO₂) with a hollow core/porous shell structure are demonstrated as effective vehicles for anti‐cancer drug delivery. While the highly porous feature of the shell allows the drug, doxorubicin(DOX), to easily pass through between the inner void space and surrounding environment of the particles, the void space in the core endows the nanocapsules with high drug loading capacity. The larger the inner hollow diameter, the higher their DOX loading capacity. A loading of 102% related to the weight of hm‐ZrO₂ is achieved by the nanocapsules with an inner diameter of 385 nm. Due to their pH‐dependent charge nature, hm‐ZrO₂ loaded DOX exhibit pH‐dependent drug releasing kinetics. A lower pH offers a faster DOX release rate from hm‐ZrO₂. Such a property makes the loaded DOX easily release from the nanocapsules when up‐taken by living cells. Although the flow cytometry reveals more uptake of hm‐ZrO₂ particles by normal cells, hm‐ZrO₂ loaded DOX release more drugs in cancer cells than in normal cells, leading to more cytotoxicity toward tumor cells and less cytotoxicity to healthy cells than free DOX.