Mechanically Activated Microcapsules for “On‐Demand” Drug Delivery in Dynamically Loaded Musculoskeletal Tissues

Delivery of biofactors in a precise and controlled fashion remains a clinical challenge. Stimuli‐responsive delivery systems can facilitate “on‐demand” release of therapeutics in response to a variety of physiologic triggering mechanisms (e.g., pH, temperature). However, few systems to date have taken advantage of mechanical inputs from the microenvironment to initiate drug release. Here, mechanically activated microcapsules (MAMCs) are designed to deliver therapeutics in response to the mechanically loaded environment of regenerating musculoskeletal tissues, with the ultimate goal of furthering tissue repair. To establish a suite of microcapsules with different thresholds for mechanoactivation, MAMC physical dimensions and composition are first manipulated, and their mechano‐response under both direct 2D compression and in 3D matrices mimicking the extracellular matrix properties and dynamic loading environment of regenerating tissue, is evaluated. To demonstrate the feasibility of this delivery system, an engineered cartilage model is used to test the efficacy of mechanically instigated release of transforming growth factor‐β3 on the chondrogenesis of mesenchymal stem cells. These data establish a novel platform by which to tune the release of therapeutics and/or regenerative factors based on the physiologic mechanical loading environment and will find widespread application in the repair and regeneration of musculoskeletal tissues.     

Multi‐Stimuli‐Responsive Microcapsules for Adjustable Controlled‐Release

Novel multi‐stimuli‐responsive microcapsules with adjustable controlled‐release characteristics are prepared by a microfluidic technique. The proposed microcapsules are composed of crosslinked chitosan acting as pH‐responsive capsule membrane, embedded magnetic nanoparticles to realize “site‐specific targeting”, and embedded temperature‐responsive sub‐microspheres serving as “micro‐valves”. By applying an external magnetic field, the prepared smart microcapsules can achieve targeting aggregation at specific sites. Due to acid‐induced swelling of the capsule membranes, the microcapsules exhibit higher release rate at specific acidic sites compared to that at normal sites with physiological pH. More importantly, through controlling the hydrodynamic size of sub‐microsphere “micro‐valves” by regulating the environment temperature, the release rate of drug molecules from the microcapsules can be flexibly adjusted. This kind of multi‐stimuli‐responsive microcapsules with site‐specific targeting and adjustable controlled‐release characteristics provides a new mode for designing “intelligent” controlled‐release systems and is expected to realize more rational drug administration.     

Fabrication of Gelatin Microgels by a “Cast” Strategy for Controlled Drug Release

In this paper, we propose a “casting” strategy to prepare intrinsically fluorescent, uniform and porous gelatin microgels with multi‐responsiveness. Gelatin microgels with tunable size were obtained by copying the structure of a porous CaCO₃ template. The diameter of the gelatin microgels was sensitive to salt concentration and pH. Doxorubicin and Rhodamine B as model drugs were loaded into the microgels via electrostatic interaction and release of the payload was triggered by changing the salt concentration and pH, respectively. Cell experiments demonstrated that the gelatin microgels had an excellent biocompatibility and biodegradability. The merits of gelatin microgels such as tunable size, biocompatibility, and stimulus responsive upload and release of positively charged small molecules will permit the microgels as excellent carriers for drug delivery. The whole manufacturing process is furthermore environmental‐friendly involving no organic solvents and surfactants.     

A Drug‐Self‐Gated Mesoporous Antitumor Nanoplatform Based on pH‐Sensitive Dynamic Covalent Bond

To achieve on‐demand drug release, mesoporous silica nanocarriers as antitumor platforms generally need to be gated with stimuli‐responsive capping agents. Herein, a “smart” mesoporous nanocarrier that is gated by the drug itself through a pH‐sensitive dynamic benzoic–imine covalent bond is demonstrated. The new system, which tactfully bypasses the use of auxiliary capping agents, could also exhibit desirable drug release at tumor tissues/cells and enhanced tumor inhibition. Moreover, a facile dynamic PEGylation via benzoic–imine bond further endows the drug‐self‐gated nanocarrier with tumor extracellular pH‐triggered cell uptake and improves therapeutic efficiency in vivo. In short, the paradigm shift in capping agents here will simplify mesoporous nanomaterials as intelligent drug carriers for cancer therapy. Moreover, the self‐gated strategy in this work also shows general potential for self‐controlled delivery of natural biomolecules, for example, DNA/RNA, peptides, and proteins, due to their intrinsic amino groups.     

Near‐Infrared Light‐Encoded Orthogonally Triggered and Logical Intracellular Release Using Gold Nanocage@Smart Polymer Shell

Gold nanocages (AuNCs) with hollow interiors, porous walls, and tunable localized surface plasmon resonance (LSPR) peaks in the NIR region represent a promising platform for therapeutic applications, and can be used for orthogonally triggered release by choosing the right laser according to the AuNC's LSPR. AuNCs are prepared with different LSPRs and covered with a smart polymer shell. Laser irradiation in resonance with the LSPR can trigger the release of a pre‐loaded effector. As a proof of concept, enzyme and substrate (prodrug) are selectively released from two different AuNCs. Enzymatic reactions only occur after successful opening of both types of AuNC capsules. The system acts as an “AND” logic gate. Furthermore, if the AuNC is loaded with isoenzyme or enzyme inhibitor, an “OR” or “INHIBIT” logic gate operation is achieved. To the best of our knowledge, no reports have combined NIR light‐encoded orthogonally triggered release with “prodrug” activation processes to realize defined different logic operations for regulating the dosage of active drug in a specific region. The design is simple and spatial/temporal to control, and provides new insights into developing NIR light‐encoded, logically controlled, intracellular release systems.     

Sequential Enzyme Activation of a “Pro‐Staramine”‐Based Nanomedicine to Target Tumor Mitochondria

Blocking cancer metabolism represents an attractive therapeutic strategy for cancer treatment. However, the lack of selective mitochondria targeting compromises the efficacy and safety of antimetabolic agents. Given that β‐glucuronidase (β‐G) is overexpressed in the tumor extracellular microenvironment and intracellular endosomes and lysosomes, a new concept of “pro‐staramine” is proposed to achieve multistage tumor mitochondrial targeting. The pro‐staramine, namely GluAcNA, is engineered by conjugating a β‐glucuronic acid to staramine via a “seamless” linker. When exposed to β‐G, the β‐glucuronic acid in GluAcNA can be hydrolyzed, followed by a rapid 1,6‐self‐elimination of the “seamless”, thus transforming anionic GluAcNA to cationic staramine. Liposomes containing GluAcNA (GluAcNA‐Lip) show long‐circulating characteristics and undergo a sequentially β‐G‐triggered activation, resulting in a cation‐driven mitochondrial accumulation. The multistage mitochondrial targeting and the promising antitumoral efficacy of GluAcNA‐Lip are validated by employing lonidamine as a model drug.     

Smart Supramolecular “Trojan Horse”‐Inspired Nanogels for Realizing Light‐Triggered Nuclear Drug Influx in Drug‐Resistant Cancer Cells

Efficient nuclear delivery of anticancer drugs evading drug efflux transporters (DETs) on the plasma and nuclear membranes of multidrug‐resistant cancer cells is highly challenging. Here, smart nanogels are designed via a one‐step self‐assembly of three functional components including a biocompatible copolymer, a fluorescent organosilica nanodot, and a photodegradable near‐infrared (NIR) dye indocyanine green (ICG). The rationally designed nanogels have high drug encapsulation efficiency (≈99%) for anticancer drug doxorubicin (Dox), self‐traceability for bioimaging, proper size for passive tumor targeting, prolonged blood circulation time for enhanced drug accumulation in tumor, and photocontrolled disassemblability. Moreover, the Dox‐loaded nanogels can effectively kill multidrug‐resistant cells via two steps: 1) They behave like a “Trojan horse” to escape from the DETs on the plasma membrane for efficiently transporting the anticancer “soldier” (Dox) into the cytoplasm and preventing the drugs from being excreted from the cells; 2) Upon NIR light irradiation, the photodegradation of ICG leads to the disassembly of the nanogels to release massive Dox molecules, which can evade the DETs on the nuclear membrane to exert their intranuclear efficacy in multidrug‐resistant cells. Combined with their excellent biocompatibility, the nanogels may provide an alternative solution for overcoming cancer multidrug resistance.     

Multi‐Caged IrOx for Facile Preparation of “Six‐in‐One” Nanoagent for Subcutaneous and Lymphatic Tumors Inhibition against Recurrence and Metastasis

Single nanocarriers with intrinsic characteristics of diagnosis, effective therapy against solid malignancies with fatal metastasis, and tumor microenvironment regulation are promising in construction of a simple and effective multimode nanotheranostic system. Herein, multi‐caged IrO_x nanocarriers are fabricated by direct thermal hydrolysis strategy, which exhibit good sono‐photodynamic response, outstanding gemstone spectral computed tomography, and photoacoustic (PA) imaging capabilities, universal loading, and pinpoint drug release properties. As a proof of concept, a gemstone spectral computed tomography/PA/fluorescence imaging–guided oxygen self‐sufficient sono‐photo‐chemotherapy nanoagent by simple loading of doxorubicin is constructed. The remarkable synergistic therapy and excellent hypoxia releasing capabilities can remove both subcutaneous and sentinel lymph nodes metastasis tumors, and effectively suppress tumor recurrence and lung metastasis, thus greatly prolonging survival time. The study provides an attractive candidate to construct a “six‐in‐one” (tri‐modal therapies and three imaging modalities) tumor theranostic system.     

Multifunctional Up‐Converting Nanocomposites with Smart Polymer Brushes Gated Mesopores for Cell Imaging and Thermo/pH Dual‐Responsive Drug Controlled Release

Multifunctional nanocarriers based on the up‐conversion luminescent nanoparticles of NaYF₄:Yb³⁺/Er³⁺ core (UCNPs) and thermo/pH‐coupling sensitive polymer poly[(N‐isopropylacrylamide)‐co‐(methacrylic acid)] (P(NIPAm‐co‐MAA)) gated mesoporous silica shell are reported for cancer theranostics, including fluorescence imaging, and for controlled drug release for therapy. The as‐synthesized hybrid nanospheres UCNPs@mSiO₂‐P(NIPAm‐co‐MAA) show bright green up‐conversion fluorescence under 980 nm laser excitation and the thermo/pH‐sensitive polymer is active as a “valve” to moderate the diffusion of the embedded drugs in‐and‐out of the pore channels of the silica container. The anticancer drug doxorubicin hydrochloride (DOX) can be absorbed into UCNPs@mSiO₂‐P(NIPAm‐co‐MAA) nanospheres and the composite drug delivery system (DDS) shows a low level of leakage at low temperature/high pH values but significantly enhanced release at higher temperature/lower pH values, exhibiting an apparent thermo/pH controlled “on‐off” drug release pattern. The as‐prepared UCNPs@mSiO₂‐P(NIPAm‐co‐MAA) hybrid nanospheres can be used as bioimaging agents and biomonitors to track the extent of drug release. The reported multifunctional nanocarriers represent a novel and versatile class of platform for simultaneous imaging and stimuli‐responsive controlled drug delivery.     

A pH‐Responsive Gating Membrane System with Pumping Effects for Improved Controlled Release

In this study, we report on a novel composite membrane system for pH‐responsive controlled release, which is composed of a porous membrane with linear grafted, positively pH‐responsive polymeric gates acting as functional valves, and a crosslinked, negatively pH‐responsive hydrogel inside the reservoir working as a functional pumping element. The proposed system features a large responsive release rate that goes effectively beyond the limit of concentration‐driven diffusion due to the pumping effects of the negatively pH‐responsive hydrogel inside the reservoir. The pH‐responsive gating membranes were prepared by grafting poly(methacrylic acid) (PMAA) linear chains onto porous polyvinylidene fluoride (PVDF) membrane substrates using a plasma‐graft pore‐filling polymerization, and the crosslinked poly(N,N‐dimethylaminoethyl methacrylate) (PDM) hydrogels were synthesized by free radical polymerization. The volume phase‐transition characteristics of PMAA and PDM were opposite. The proposed system opens new doors for pH‐responsive “smart” or “intelligent” controlled‐release systems, which are highly attractive for drug‐delivery systems, chemical carriers, sensors, and so on.     

“Tissue Papers” from Organ‐Specific Decellularized Extracellular Matrices

Using an innovative, tissue‐independent approach to decellularized tissue processing and biomaterial fabrication, the development of a series of “tissue papers” derived from native porcine tissues/organs (heart, kidney, liver, muscle), native bovine tissue/organ (ovary and uterus), and purified bovine Achilles tendon collagen as a control from decellularized extracellular matrix particle ink suspensions cast into molds is described. Each tissue paper type has distinct microstructural characteristics as well as physical and mechanical properties, is capable of absorbing up to 300% of its own weight in liquid, and remains mechanically robust (E = 1–18 MPa) when hydrated; permitting it to be cut, rolled, folded, and sutured, as needed. In vitro characterization with human mesenchymal stem cells reveals that all tissue paper types support cell adhesion, viability, and proliferation over four weeks. Ovarian tissue papers support mouse ovarian follicle adhesion, viability, and health in vitro, as well as support, and maintain the viability and hormonal function of nonhuman primate and human follicle‐containing, live ovarian cortical tissues ex vivo for eight weeks postmortem. “Tissue papers” can be further augmented with additional synthetic and natural biomaterials, as well as integrated with recently developed, advanced 3D‐printable biomaterials, providing a versatile platform for future multi‐biomaterial construct manufacturing.     

Engineering Inorganic Nanoemulsions/Nanoliposomes by Fluoride‐Silica Chemistry for Efficient Delivery/Co‐Delivery of Hydrophobic Agents

A novel drug‐formulation protocol is developed to solve the delivery problem of hydrophobic drug molecules by using inorganic mesoporous silica nanocapsules (IMNCs) as an alternative to traditional organic emulsions and liposomes while preserving the advantages of inorganic materials. The unique structures of IMNCs are engineered by a novel fluoride‐silica chemistry based on a structural difference‐based selective etching strategy. The prepared IMNCs combine the functions of organic nanoemulsions or nanoliposomes with the properties of inorganic materials. Various spherical nanostructures can be fabricated simply by varying the synthetic parameters. The drug loading amount of a typical highly hydrophobic anticancer drug‐camptothecin (CPT) in IMNCs reaches as high as 35.1 wt%. The intracellular release of CPT from carriers is demonstrated in situ. In addition, IMNCs can play the role of organic nanoliposome (multivesicular liposome) in co‐encapsulating and co‐delivering hydrophobic (CPT) and hydrophilic (doxorubicin, DOX) anticancer drugs simultaneously. The co‐delivery of multi‐drugs in the same carrier and the intracellular release of the drug combinations enables a drug delivery system with efficient enhanced chemotherapeutic effect for DOX‐resistant MCF‐7/ADR cancer cells. The special IMNCs‐based “inorganic nanoemulsion”, as a proof‐of‐concept, can also be employed successfully to encapsulate and deliver biocompatible hydrophobic perfluorohexane (PFH) molecules for high intensity focused ultrasound (HIFU) synergistic therapy ex vivo and in vivo. Based on this novel design strategy, a wide range of inorganic material systems with similar “inorganic nanoemulsion or nanoliposome” functions will be developed to satisfy varied clinical requirements.     

A Conditionally Releasable “Do not Eat Me” CD47 Signal Facilitates Microglia‐Targeted Drug Delivery for the Treatment of Alzheimer's Disease

Efficient brain drug delivery has been a challenge in the treatment of Alzheimer's disease (AD) and other brain disorders as blood‐brain barrier (BBB) impedes most drugs to reach brain. To overcome this obstacle, a novel poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with CD47 extracellular domain via reactive oxygen species (ROS)‐responsive phenylborate ester bond exhibiting “do not eat me” signal and BBB penetrating peptide CRTIGPSVC (CRT) and microglia modulation agent Nec‐1s encapsulated in it is developed. The experimental results show that the designed nanoparticle efficiently increases its half‐life in blood circulation by preventing engulfment via phagocytes, and enhances its brain distribution by synergistic effect of CD47 and CRT. The high level of ROS in mouse brain releases CD47 from the nanoparticles and the resultant particles are effectively phagocytized by resident microglia. The engulfed Nec‐1s modulates pathological microglia to a beneficial state, which reduces Aβ burden, microgliosis and astrocytosis, decreases cytokine production and oxidative stress in the brains of AD mice, and finally attenuates cognition deficits and synapse loss. The results first demonstrate that the conditionally releasable “do not eat me” CD47 signal remarkably facilitates microglia‐targeted drug delivery and warrants further study to develop therapeutic agent for AD treatment.     

Controllable Stiffness Origami “Skeletons” for Lightweight and Multifunctional Artificial Muscles

Flexible, material‐based, artificial muscles enable compliant and safe technologies for human–machine interaction devices and adaptive soft robots, yet there remain long‐term challenges in the development of artificial muscles capable of mimicking flexible, controllable, and multifunctional human activity. Inspired by human limb's activity strategy, combining muscles' adjustable stiffness and joints' origami folding, controllable stiffness origami “skeletons,” which are created by laminar jamming and origami folding of multiple layers of flexible sandpaper, are embedded into a common monofunctional vacuumed‐powered cube‐shaped (CUBE) artificial muscle, thereby enabling the monofunctional CUBE artificial muscle to achieve lightweight and multifunctionality as well as controllable force/motion output without sacrificing its volume and shape. Successful demonstrations of arms self‐assembly and cooperatively gripping different objects and a “caterpillar” robot climbing different pipes illustrate high operational redundancy and high‐force output through “building blocks” assembly of multifunctional CUBE artificial muscles. Controllable stiffness origami “skeletons” offer a facile and low‐cost strategy to fabricate lightweight and multifunctional artificial muscles for numerous potential applications such as wearable assistant devices, miniature surgical instruments, and soft robots.     

Versatile Functionalization of the Micropatterned Hydrogel of Hyperbranched Poly(ether amine) Based on “Thiol‐yne” Chemistry

The functionalization of a hydrogel with target molecules is one of the key steps in its various applications. Here, a versatile approach is demonstrated to functionalize a micropatterned hydrogel, which is formed by “thiol‐yne” photo‐click reaction between the yne‐ended hyperbranched poly(ether amine) (hPEA‐yne) and thiol‐containing polyhedral oligomeric silsesquioxane (PEG‐POSS‐SH). By controlling the molar ratio between hPEA‐yne and PEG‐POSS‐SH, patterned hydrogels containing thiol or yne groups are obtained. A series of thiol‐based click chemistry such as “thiol‐epoxy”, “thiol‐halogen”, “thiol‐ene”, and “thiol‐isocyanate” are used to functionalize the thiol‐containing hydrogel (Gel‐1), while the yne‐containing hydrogel (Gel‐2) is functionalized through a typical copper‐catalysed alkyne‐azide reaction (CuAAC). FTIR, UV‐vis spectra and confocal laser scanning microscopy (CLSM) are used to trace these click reactions. Due to the selective adsorption to the hydrophilic dyes, the obtained patterned hydrogel of hPEA modified with fluorescence dye is further demonstrated in application for the recognition of guest molecules.     

Magnetic Liquid Marbles: Toward “Lab in a Droplet”

Liquid marbles exhibit great potential for use as miniature labs for small‐scale laboratory operations, such as experiment and measurement. While important progress has been made recently in exploring their applications as microreactions, “on‐line” measurement of the components inside the liquid still remains a challenge. Herein, it is demonstrated that “on‐line” detection can be realized on magnetic liquid marbles by taking advantage of their unique magnetic opening feature. By partially opening the particle shell, electrochemical measurement is carried out with a miniaturized three‐electrode probe and the application of this technique for quantitative measurement of dopamine is demonstrated. Fully opened magnetic liquid marble makes it feasible to detect the optical absorbance of the liquid in a transmission mode. With this optical method, a glucose assay is demonstrated. Moreover, when magnetic particle shell contains low melting point material, e.g., wax, the liquid marble shows a unique encapsulation ability to form a rigid shell after heating, which facilitates the storage of the non‐volatile ingredients. These unique features, together with the versatile use as microreactors, enable magnetic liquid marbles to function as a miniature lab (or called “lab in a droplet”), which may find applications in clinical diagnostics, biotechnology, chemical synthesis, and analytical chemistry.     

Self‐Rupturing and Hollow Microcapsules Prepared from Bio‐polyelectrolyte‐Coated Microgels

This paper reports on microcapsules obtained by layer‐by‐layer deposition of bio‐polyelectrolyte multilayers at the surface of biodegradable dextran microgels. The behavior of the layer‐by‐layer coating upon degradation of the microgel core strongly depends on the bio‐polyelectrolytes used. Two types of microcapsules, “self‐rupturing” microcapsules and “hollow” microcapsules, are presented. Self‐rupturing microcapsules are obtained when the swelling pressure of the degrading microgel core is strong enough to rupture the surrounding bio‐polyelectrolyte membrane. Self‐rupturing microcapsules could be of interest as a pulsed drug delivery system. Hollow microcapsules are obtained after applying multiple layers of bio‐polyelectrolyte that can withstand the swelling pressure of the degrading microgel core. Biomacromolecules (such as albumin and dextran) spontaneously accumulate in the hollow microcapsules prepared from dex‐HEMA microgels, which could be of interest for drug‐encapsulation purposes.     

Omniphobic “RF Paper” Produced by Silanization of Paper with Fluoroalkyltrichlorosilanes

The fabrication and properties of “fluoroalkylated paper” (“R^F paper”) by vapor‐phase silanization of paper with fluoroalkyl trichlorosilanes is reported. R^F paper is both hydrophobic and oleophobic: it repels water (θ_app^H2^O>140°), organic liquids with surface tensions as low as 28 mN m^‐1, aqueous solutions containing ionic and non‐ionic surfactants, and complex liquids such as blood (which contains salts, surfactants, and biological material such as cells, proteins, and lipids). The propensity of the paper to resist wetting by liquids with a wide range of surface tensions correlates with the length and degree of fluorination of the organosilane (with a few exceptions in the case of methyl trichlorosilane‐treated paper), and with the roughness of the paper. R^F paper maintains the high permeability to gases and mechanical flexibility of the untreated paper, and can be folded into functional shapes (e.g., microtiter plates and liquid‐filled gas sensors). When impregnated with a perfluorinated oil, R^F paper forms a “slippery” surface (paper slippery liquid‐infused porous surface, or “paper SLIPS“) capable of repelling liquids with surface tensions as low as 15 mN m^‐1. The foldability of the paper SLIPS allows the fabrication of channels and flow switches to guide the transport of liquid droplets.     

Red‐Light‐Controlled Release of Drug–Ru Complex Conjugates from Metallopolymer Micelles for Phototherapy in Hypoxic Tumor Environments

Traditional photodynamic phototherapy is not efficient for anticancer treatment because solid tumors have a hypoxic microenvironment. The development of photoactivated chemotherapy based on photoresponsive polymers that can be activated by light in the “therapeutic window” would enable new approaches for basic research and allow for anticancer phototherapy in hypoxic conditions. This work synthesizes a novel Ru‐containing block copolymer for photoactivated chemotherapy in hypoxic tumor environment. The polymer has a hydrophilic poly(ethylene glycol) block and a hydrophobic Ru‐containing block, which contains red‐light‐cleavable (650–680 nm) drug–Ru complex conjugates. The block copolymer self‐assembles into micelles, which can be efficiently taken up by cancer cells. Red light induces release of the drug–Ru complex conjugates from the micelles and this process is oxygen independent. The released conjugates inhibit tumor cell growth even in hypoxic tumor environment. Furthermore, the Ru‐containing polymer for photoactivated chemotherapy in a tumor‐bearing mouse model is applied. Photoactivated chemotherapy of the polymer micelles demonstrates efficient tumor growth inhibition. In addition, the polymer micelles do not cause any toxic side effects to mice during the treatment, demonstrating good biocompatibility of the system to the blood and healthy tissues. The novel red‐light‐responsive Ru‐containing polymer provides a new platform for phototherapy against hypoxic tumors.     

Integrated Combination Treatment Using a “Smart” Chemotherapy and MicroRNA Delivery System Improves Outcomes in an Orthotopic Colorectal Cancer Model

Mesoporous silica nanoparticles (MSN) can load and deliver potentially synergistic anticancer agents such as small molecule cytotoxics (like doxorubicin, DOX) and nucleic acids (like microRNA, miRNA). However, these cargos have different underlying chemical properties so overcoming respective intracellular delivery barriers is a key consideration. Strategies to deliver DOX from MSN frequently employ pH‐driven mechanisms that are restricted to the acidic environment of lysosomes. Conversely, strategies to deliver miRNA make use of approaches that deliberately compromise lysosomal membrane integrity to enable cytosolic delivery of the payload. To reconcile these two needs (lysosomal delivery of DOX and intracellular delivery of miRNA), a new methodology by “weaving” polyethylenimine on the MSN surface through disulfide bonds to achieve superior delivery of chemotherapy (DOX) and miRNA therapy (using miRNA‐145) is developed. Furthermore, an active targeting strategy based on a peptide ligand with affinity to glucose‐regulated protein 78 (GRP78), a cell surface protein overexpressed in colorectal carcinoma, is developed. The active targeting approach results in enhanced synergistic antitumor effect both in vitro and in vivo in an orthotopic murine model of colorectal cancer. Taken together, this work demonstrates the capability and advantages of “smart” MSN delivery systems to deliver anticancer cargo appropriately to targeted cancer cells.