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Atherosclerotic cardiovascular disease is the leading cause of mortality in the world. A driving feature of atherosclerotic plaque formation is dysfunctional efferocytosis. Because the “don’t eat me” molecule CD47 is upregulated in atherosclerotic plaque cores, CD47-blocking strategies can stimulate the efferocytic clearance of apoptotic cells and thereby help prevent the progression of plaque buildup. However, these therapies are generally costly and, in clinical and murine trials, they have resulted in side effects including anemia and reticulocytosis. Here, we developed and characterized an intracellular phagocytosis-stimulating treatment in the CD47-SIRPα pathway. We loaded a novel monocyte/macrophage-selective nanoparticle carrier system with a small molecule enzymatic inhibitor that is released in a pH-dependent manner to stimulate macrophage efferocytosis of apoptotic cell debris via the CD47-SIRPα signaling pathway. We demonstrated that single-walled carbon nanotubes (SWNTs) can selectively deliver tyrosine phosphatase inhibitor 1 (TPI) intracellularly to macrophages, which potently stimulates efferocytosis, and chemically characterized the nanocarrier. Thus, SWNT-delivered TPI can stimulate macrophage efferocytosis, with the potential to reduce or prevent atherosclerotic disease.

Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of ‘Trojan horse’ nanoparticles to prevent atherosclerotic cardiovascular disease. Single-walled carbon nanotubes can restore phagocytotic properties of macrophages in artherosclerotic plaques to promote plaque clearance and combat artherosclerosis.

Nanoparticles promise to advance strategies to treat vascular disease. Since being harnessed by the cancer field to deliver safer and more effective chemotherapeutics, nanoparticles have been translated into applications for cardiovascular disease. Systemic exposure and drug-drug interactions remain a concern for nearly all cardiovascular therapies, including statins, antithrombotic, and thrombolytic agents. Moreover, off-target effects and poor bioavailability have limited the development of completely new approaches to treat vascular disease. Through the rational design of nanoparticles, nano-based delivery systems enable more efficient delivery of a drug to its therapeutic target or even directly to the diseased site, overcoming biological barriers and enhancing a drug’s therapeutic index. In addition, advances in molecular imaging have led to the development of theranostic nanoparticles that may simultaneously act as carriers of both therapeutic and imaging payloads. The following is a summary of nanoparticle therapy for atherosclerosis, thrombosis, and restenosis and an overview of recent major advances in the targeted treatment of vascular disease.

We have synthesized polypyrrole nanoparticles using three different oxidizing agents (hydrogen peroxide, chloroauric acid and ferric chloride) and shown that films assembled from these nanoparticles have significantly different drug release profiles. When ferric chloride is used as the oxidizing agent, it is possible to release drugs at voltages as low as -0.05 V, almost an order of magnitude lower than typically used voltages. These ultra-low voltage responsive nanoparticles widen the window of operation of conducting polymers and enable delivery of redox active drugs. As an example, we have shown pulsed release of the chemotherapeutic methotrexate at voltages as low as -0.075 V, demonstrating the potential application of these nanoparticles in cancer treatment. We have also verified the anti-tumor efficacy of the released drug using PC12 cell cultures.

Catheter-based intra-arterial drug therapies have proven effective for a range of oncologic, neurologic, and cardiovascular applications. However, these procedures are limited by their invasiveness and relatively broad drug spatial distribution. The ideal technique for local pharmacotherapy would be noninvasive and would flexibly deliver a given drug to any region of the body with high spatial and temporal precision. Combining polymeric perfluorocarbon nanoemulsions with existent clinical focused ultrasound systems could in principle meet these needs, but it has not been clear whether these nanoparticles could provide the necessary drug loading, stability, and generalizability across a range of drugs, beyond a few niche applications. Here, we develop polymeric perfluorocarbon nanoemulsions into a generalized platform for ultrasound-targeted delivery of hydrophobic drugs with high potential for clinical translation. We demonstrate that a wide variety of drugs may be effectively uncaged with ultrasound using these nanoparticles, with drug loading increasing with hydrophobicity. We also set the stage for clinical translation by delineating production protocols that are scalable and yield sterile, stable, and optimized ultrasound-activated drug-loaded nanoemulsions. Finally, we exhibit a new potential application of these nanoemulsions for local control of vascular tone. This work establishes the power of polymeric perfluorocarbon nanoemulsions as a clinically-translatable platform for efficacious, noninvasive, and localized ultrasonic drug uncaging for myriad targets in the brain and body.

A wirelessly powered implantable device is proposed for fully programmable and localized drug delivery. The implant is powered using an external ultrasonic transmitter and operates at < 5% of the FDA diagnostic ultrasound intensity limit. Drug release is achieved through electrical stimulation of drug-loaded polypyrrole nanoparticles. A design methodology for the implant electronics is presented and experimentally demonstrated to be accurate in predicting the concentration of the released drug. To the best of our knowledge, this is the first ultrasonically powered implantable device platform for targeted drug delivery using electroresponsive polymers. The active area of the implant electronics is just 3 mm × 5 mm.

Conducting polymers present an opportunity for developing programmable, adjustable, spatially, and temporally controllable drug delivery systems. While several small molecule drugs have been released from thin conductive polymeric films successfully, delivering large molecule therapeutics, such as polypeptides and nucleic acids, has remained a significant challenge. Poor drug loading (∼ng cm−2) of thin films coupled with film instability has, in many cases, made conducting polymer films refractory to clinical development. To address these limitations, we have utilized conductive polymer nanoparticulate backbones to controllably release insulin, a high molecular weight, clinically relevant polypeptide. We find that the interaction between insulin and the polymer scaffold can be described by a simple Langmuir-type adsorption model. By modifying the ratio of the amount of nanoparticles to the amount of insulin, we have obtained drug loading percentages estimated to be as high as 51 wt% percent. In vivo experiments in mice confirmed retained bioactivity of the released insulin after electrical stimulation.

The potential of electroresponsive conducting polymer nanoparticles to be used as general drug delivery systems that allow electrically pulsed, linearly scalable, and on demand release of incorporated drugs is demonstrated. As examples, facile release from polypyrrole nanoparticles is shown for fluorescein, a highly water-soluble model compound, piroxicam, a lipophilic small molecule drug, and insulin, a large hydrophilic peptide hormone. The drug loading is about 13 wt% and release is accomplished in a few seconds by applying a weak constant current or voltage. To identify the parameters that should be finely tuned to tailor the carrier system for the release of the therapeutic molecule of interest, a systematic study of the factors that affect drug delivery is performed, using fluorescein as a model compound. The parameters studied include current, time, voltage, pH, temperature, particle concentration, and ionic strength. Results indicate that there are several degrees of freedom that can be optimized for efficient drug delivery. The ability to modulate linearly drug release from conducting polymers with the applied stimulus can be utilized to design programmable and minimally invasive drug delivery devices.