A Size‐Selective Intracellular Delivery Platform

Identifying and separating a subpopulation of cells from a heterogeneous mixture are essential elements of biological research. Current approaches require detailed knowledge of unique cell surface properties of the target cell population. A method is described that exploits size differences of cells to facilitate selective intracellular delivery using a high throughput microfluidic device. Cells traversing a constriction within this device undergo a transient disruption of the cell membrane that allows for cytoplasmic delivery of cargo. Unique constriction widths allow for optimization of delivery to cells of different sizes. For example, a 4 μm wide constriction is effective for delivery of cargo to primary human T‐cells that have an average diameter of 6.7 μm. In contrast, a 6 or 7 μm wide constriction is best for large pancreatic cancer cell lines BxPc3 (10.8 μm) and PANC‐1 (12.3 μm). These small differences in cell diameter are sufficient to allow for selective delivery of cargo to pancreatic cancer cells within a heterogeneous mixture containing T‐cells. The application of this approach is demonstrated by selectively delivering dextran‐conjugated fluorophores to circulating tumor cells in patient blood allowing for their subsequent isolation and genomic characterization.     

Self‐Powered Intracellular Drug Delivery by a Biomechanical Energy‐Driven Triboelectric Nanogenerator

Nondestructive, high‐efficiency, and on‐demand intracellular drug/biomacromolecule delivery for therapeutic purposes remains a great challenge. Herein, a biomechanical‐energy‐powered triboelectric nanogenerator (TENG)‐driven electroporation system is developed for intracellular drug delivery with high efficiency and minimal cell damage in vitro and in vivo. In the integrated system, a self‐powered TENG as a stable voltage pulse source triggers the increase of plasma membrane potential and membrane permeability. Cooperatively, the silicon nanoneedle‐array electrode minimizes cellular damage during electroporation via enhancing the localized electrical field at the nanoneedle–cell interface and also decreases plasma membrane fluidity for the enhancement of molecular influx. The integrated system achieves efficient delivery of exogenous materials (small molecules, macromolecules, and siRNA) into different types of cells, including hard‐to‐transfect primary cells, with delivery efficiency up to 90% and cell viability over 94%. Through simple finger friction or hand slapping of the wearable TENGs, it successfully realizes a transdermal biomolecule delivery with an over threefold depth enhancement in mice. This integrated and self‐powered system for active electroporation drug delivery shows great prospect for self‐tuning drug delivery and wearable medicine.     

Multifarious Transit Gates for Programmable Delivery of Bio‐functionalized Matters

Programmable delivery of biological matter is indispensable for the massive arrays of individual objects in biochemical and biomedical applications. Although a digital manipulation of single cells has been implemented by the integrated circuits of micromagnetophoretic patterns with current wires, the complex fabrication process and multiple current operation steps restrict its practical application for biomolecule arrays. Here, a convenient approach using multifarious transit gates is proposed, for digital manipulation of biofunctionalized microrobotic particles that can pass through the local energy barriers by a time‐dependent pulsed magnetic field instead of multiple current wires. The multifarious transit gates including return, delay, and resistance linear gates, as well as dividing, reversed, and rectifying T‐junction gates, are investigated theoretically and experimentally for the programmable manipulation of microrobotic particles. The results demonstrate that, a suitable angle of the gating field at a suitable time zone is crucial to implement digital operations at integrated multifarious transit gates along bifurcation paths to trap microrobotic particles in specific apartments, paving the way for flexible on‐chip arrays of biomolecules and cells.     

Targeted Liposome‐Loaded Microbubbles for Cell‐Specific Ultrasound‐Triggered Drug Delivery

One of the main problems in cancer treatment is disease relapse through metastatic colonization, which is caused by circulating tumor cells (CTCs). This work reports on liposome‐loaded microbubbles targeted to N‐cadherin, a cell–cell adhesion molecule expressed by CTCs. It is shown that such microbubbles can indeed bind to N‐cadherin at the surface of HMB2 cells. Interestingly, in a mixture of cells with and without N‐cadherin expression, binding of the liposome‐loaded microbubbles mainly occurs to the N‐cadherin‐expressing cells. Importantly, applying ultrasound results in the intracellular delivery of a model drug (loaded in the liposomes) in the N‐cadherin‐expressing cells only. As described in this paper, such liposome‐loaded microbubbles may find application as theranostics and in devices aimed for the specific killing of CTCs in blood.     

Protein‐Based Nanomedicine Platforms for Drug Delivery

Protein‐based nanomedicine platforms for drug delivery comprise naturally self‐assembled protein subunits of the same protein or a combination of proteins making up a complete system. They are ideal for drug‐delivery platforms due to their biocompatibility and biodegradability coupled with low toxicity. A variety of proteins have been used and characterized for drug‐delivery systems, including the ferritin/apoferritin protein cage, plant‐derived viral capsids, the small Heat shock protein (sHsp) cage, albumin, soy and whey protein, collagen, and gelatin. There are many different types and shapes that have been prepared to deliver drug molecules using protein‐based platforms, including various protein cages, microspheres, nanoparticles, hydrogels, films, minirods, and minipellets. The protein cage is the most newly developed biomaterial for drug delivery and therapeutic applications. The uniform size, multifunctionality, and biodegradability push it to the frontier of drug delivery. In this Review, the recent strategic development of drug delivery is discussed with emphasis on polymer‐based, especially protein‐based, nanomedicine platforms for drug delivery. The advantages and disadvantages are also discussed for each type of protein‐based drug‐delivery system.

     

A Dual‐Responsive Mesoporous Silica Nanoparticle for Tumor‐Triggered Targeting Drug Delivery

A novel pH‐ and redox‐ dual‐responsive tumor‐triggered targeting mesoporous silica nanoparticle (TTTMSN) is designed as a drug carrier. The peptide RGDFFFFC is anchored on the surface of mesoporous silica nanoparticles via disulfide bonds, which are redox‐responsive, as a gatekeeper as well as a tumor‐targeting ligand. PEGylated technology is employed to protect the anchored peptide ligands. The peptide and monomethoxypolyethylene glycol (MPEG) with benzoic‐imine bond, which is pH‐sensitive, are then connected via “click” chemistry to obtain TTTMSN. In vitro cell research demonstrates that the targeting property of TTTMSN is switched off in normal tissues with neutral pH condition, and switched on in tumor tissues with acidic pH condition after removing the MPEG segment by hydrolysis of benzoic‐imine bond under acidic conditions. After deshielding of the MPEG segment, the drug‐loaded nanoparticles are easily taken up by tumor cells due to the exposed peptide targeting ligand, and subsequently the redox signal glutathione in tumor cells induces rapid drug release intracellularly after the cleavage of disulfide bond. This novel intelligent TTTMSN drug delivery system has great potential for cancer therapy.     

Bioinspired Diselenide‐Bridged Mesoporous Silica Nanoparticles for Dual‐Responsive Protein Delivery

Controlled delivery of protein therapeutics remains a challenge. Here, the inclusion of diselenide‐bond‐containing organosilica moieties into the framework of silica to fabricate biodegradable mesoporous silica nanoparticles (MSNs) with oxidative and redox dual‐responsiveness is reported. These diselenide‐bridged MSNs can encapsulate cytotoxic RNase A into the 8–10 nm internal pores via electrostatic interaction and release the payload via a matrix‐degradation controlled mechanism upon exposure to oxidative or redox conditions. After surface cloaking with cancer‐cell‐derived membrane fragments, these bioinspired RNase A‐loaded MSNs exhibit homologous targeting and immune‐invasion characteristics inherited from the source cancer cells. The efficient in vitro and in vivo anti‐cancer performance, which includes increased blood circulation time and enhanced tumor accumulation along with low toxicity, suggests that these cell‐membrane‐coated, dual‐responsive degradable MSNs represent a promising platform for the delivery of bio‐macromolecules such as protein and nucleic acid therapeutics.     

Rationally Designed DNA‐Origami Nanomaterials for Drug Delivery In Vivo

The recent decades have seen a surge of new nanomaterials designed for efficient drug delivery. DNA nanotechnology has been developed to construct sophisticated 3D nanostructures and artificial molecular devices that can be operated at the nanoscale, giving rise to a variety of programmable functions and fascinating applications. In particular, DNA‐origami nanostructures feature rationally designed geometries and precise spatial addressability, as well as marked biocompatibility, thus providing a promising candidate for drug delivery. Here, the recent successful efforts to employ self‐assembled DNA‐origami nanostructures as drug‐delivery vehicles are summarized. The remaining challenges and open opportunities are also discussed.