Small interfering RNA (siRNA) is a powerful tool for gene silencing that has been used for a wide range of biomedical applications, but there are many challenges facing its therapeutic use in vivo. Here, we report on a platelet cell membrane-coated metal-organic framework (MOF) nanodelivery platform for the targeted delivery of siRNA in vivo. The MOF core is capable of high loading yields, and its pH sensitivity enables endosomal disruption upon cellular uptake. The cell membrane coating provides a natural means of biointerfacing with disease substrates. It is shown that high silencing efficiency can be achieved in vitro against multiple target genes. Using a murine xenograft model, significant antitumor targeting and therapeutic efficacy are observed. Overall, the biomimetic nanodelivery system presented here provides an effective means of achieving gene silencing in vivo and could be used to expand the applicability of siRNA across a range of disease-relevant applications.

Platelets possess distinct surface moieties responsible for modulating their adhesion to various disease-relevant substrates involving vascular damage, immune evasion, and pathogen interactions. Such broad biointerfacing capabilities of platelets have inspired the development of platelet-mimicking drug carriers that preferentially target drug payloads to disease sites for enhanced therapeutic efficacy. Among these carriers, platelet membrane-coated nanoparticles (denoted 'PNPs') made by cloaking synthetic substrates with the plasma membrane of platelets have emerged recently. Their 'top-down' design combines the functionalities of natural platelet membrane and the engineering flexibility of synthetic nanomaterials, which together create synergy for effective drug delivery and novel therapeutics. Herein, we review the recent progress of engineering PNPs with different structures for targeted drug delivery, focusing on three areas, including targeting injured blood vessels to treat vascular diseases, targeting cancer cells for cancer treatment and detection, and targeting drug-resistant bacteria to treat infectious diseases. Overall, current studies have established PNPs as versatile nanotherapeutics for drug targeting with strong potentials to improve the treatment of various diseases.

As numerous diseases are associated with increased local inflammation, directing drugs to the inflamed sites can be a powerful therapeutic strategy. One of the common characteristics of inflamed endothelial cells is the up-regulation of vascular cell adhesion molecule-1 (VCAM-1). Here, the specific affinity between very late antigen-4 (VLA-4) and VCAM-1 is exploited to produce a biomimetic nanoparticle formulation capable of targeting inflammation. The plasma membrane from cells genetically modified to constitutively express VLA-4 is coated onto polymeric nanoparticle cores, and the resulting cell membrane-coated nanoparticles exhibit enhanced affinity to target cells that overexpress VCAM-1 in vitro. A model anti-inflammatory drug, dexamethasone, is encapsulated into the nanoformulation, enabling improved delivery of the payload to inflamed lungs and significant therapeutic efficacy in vivo. Overall, this work leverages the unique advantages of biological membrane coatings to engineer additional targeting specificities using naturally occurring target-ligand interactions.

We report cellular nanosponges as an effective medical countermeasure to the SARS-CoV-2 virus. Two types of cellular nanosponges are made of the plasma membranes derived from human lung epithelial type II cells or human macrophages. These nanosponges display the same protein receptors, both identified and unidentified, required by SARS-CoV-2 for cellular entry. It is shown that, following incubation with the nanosponges, SARS-CoV-2 is neutralized and unable to infect cells. Crucially, the nanosponge platform is agnostic to viral mutations and potentially viral species, as well. As long as the target of the virus remains the identified host cell, the nanosponges will be able to neutralize the virus.

Blood transfusion is oftentimes required for patients suffering from acute trauma or undergoing surgical procedures in order to help maintain the bodys oxygen levels. The continued demand worldwide for blood products is expected to put significant strain on available resources and infrastructure. Unfortunately, efforts to develop viable alternatives to human red blood cells for transfusion are generally unsuccessful. Here, a hybrid natural-synthetic nanodelivery platform that combines the biocompatibility of the natural RBC membrane with the oxygen-carrying ability of perfluorocarbons is reported. The resulting formulation can be stored long-term and exhibits a high capacity for oxygen delivery, helping to mitigate the effects of hypoxia in vitro. In an animal model of hemorrhagic shock, mice are resuscitated at an efficacy comparable to whole blood infusion. By leveraging the advantageous properties of its constituent parts, this biomimetic oxygen delivery system may have the potential to address a critical need in the clinic.

Intratumoral immunotherapy is an emerging modality for the treatment of solid tumors. Toll-like receptor (TLR) agonists have shown promise for eliciting immune responses, but systemic administration often results in the development of adverse side effects. Herein, we investigate whether localized delivery of the TLR agonist, resiquimod (R848), via platelet membrane-coated nanoparticles (PNP-R848) elicits antitumor responses. The membrane coating provides a means of enhancing interactions with the tumor microenvironment, thereby maximizing the activity of R848. Intratumoral administration of PNP-R848 strongly enhances local immune activation and leads to complete tumor regression in a colorectal tumor model, while providing protection against repeated tumor re-challenges. Moreover, treatment of an aggressive breast cancer model with intratumoral PNP-R848 delays tumor growth and inhibits lung metastasis. Our findings highlight the promise of locally delivering immunostimulatory payloads using biomimetic nanocarriers, which possess advantages such as enhanced biocompatibility and natural targeting affinities.

Bioinspired microrobots capable of actively moving in biological fluids have attracted considerable attention for biomedical applications because of their unique dynamic features that are otherwise difficult to achieve by their static counterparts. Here we use click chemistry to attach antibiotic-loaded neutrophil membrane-coated polymeric nanoparticles to natural microalgae, thus creating hybrid microrobots for the active delivery of antibiotics in the lungs in vivo. The microrobots show fast speed (>110 µm s^-1) in simulated lung fluid and uniform distribution into deep lung tissues, low clearance by alveolar macrophages and superb tissue retention time (>2 days) after intratracheal administration to test animals. In a mouse model of acute Pseudomonas aeruginosa pneumonia, the microrobots effectively reduce bacterial burden and substantially lessen animal mortality, with negligible toxicity. Overall, these findings highlight the attractive functions of algae-nanoparticle hybrid microrobots for the active in vivo delivery of therapeutics to the lungs in intensive care unit settings.

The combination of immunotherapy with other forms of treatment is an emerging strategy for boosting antitumor responses. By combining multiple modes of action, these combinatorial therapies can improve clinical outcomes through unique synergisms. Here, a microrobot-based strategy that integrates tumor tissue disruption with biological stimulation is shown for cancer immunotherapy. The microrobot is fabricated by loading bacterial outer membrane vesicles onto a self-propelling micromotor, which can react with water to generate a propulsion force. When administered intratumorally to a solid tumor, the disruption of the local tumor tissue coupled with the delivery of an immunostimulatory payload leads to complete tumor regression. Additionally, treatment of the primary tumor results in the simultaneous education of the host immune system, enabling it to control the growth of distant tumors. Overall, this work introduces a distinct application of microrobots in cancer immunotherapy and offers an attractive strategy for amplifying cancer treatment efficacy when combined with conventional therapies.

Continuous monitoring of the central-blood-pressure waveform from deeply embedded vessels, such as the carotid artery and jugular vein, has clinical value for the prediction of all-cause cardiovascular mortality. However, existing non-invasive approaches, including photoplethysmography and tonometry, only enable access to the superficial peripheral vasculature. Although current ultrasonic technologies allow non-invasive deep-tissue observation, unstable coupling with the tissue surface resulting from the bulkiness and rigidity of conventional ultrasound probes introduces usability constraints. Here, we describe the design and operation of an ultrasonic device that is conformal to the skin and capable of capturing blood-pressure waveforms at deeply embedded arterial and venous sites. The wearable device is ultrathin (240 μm) and stretchable (with strains up to 60%), and enables the non-invasive, continuous and accurate monitoring of cardiovascular events from multiple body locations, which should facilitate its use in a variety of clinical environments.

Electrical impulse generation and its conduction within cells or cellular networks are the cornerstone of electrophysiology. However, the advancement of the field is limited by sensing accuracy and the scalability of current recording technologies. Here we describe a scalable platform that enables accurate recording of transmembrane potentials in electrogenic cells. The platform employs a three-dimensional high-performance field-effect transistor array for minimally invasive cellular interfacing that produces faithful recordings, as validated by the gold standard patch clamp. Leveraging the high spatial and temporal resolutions of the field-effect transistors, we measured the intracellular signal conduction velocity of a cardiomyocyte to be 0.182 m s^-1, which is about five times the intercellular velocity. We also demonstrate intracellular recordings in cardiac muscle tissue constructs and reveal the signal conduction paths. This platform could provide new capabilities in probing the electrical behaviours of single cells and cellular networks, which carries broad implications for understanding cellular physiology, pathology and cell-cell interactions.