Year: 2025
Type: editorial
Abstract: This editorial refers to ‘Targeted delivery of TAPI-1 via biomimetic nanoparticles ameliorates post-infarct left ventricle function and remodelling’, by Q. Chen et al., https://doi.org/10.1093/cvr/cvaf039. The delivery of drugs using nanoparticles to disease sites, such as cancer and heart disease, holds tremendous potential in medicine. However, nano-based drug delivery has been challenged by the enormous variability in efficacy due to heterogeneous accumulation at target sites.1,2 Many earlier and current targeting strategies have relied upon phenomena such as the enhanced permeability and retention effect,3 which requires increased blood vessel leakiness. Still, though this effect is highly variable, targeted delivery remains a promising avenue. Rather than directly targeting disease sites or cells—an approach that has struggled to achieve reliable or sufficient nanoparticle accumulation—research groups are increasingly asking the question, ‘what if we leverage the immune system’s natural trafficking capabilities?’ Certain immune cells, shaped by evolution, are intrinsically adept at trafficking to disease sites. Studies have shown that nanoparticles designed to target these cells, exploiting their natural homing abilities, can as a ‘Trojan Horse’ deliver drugs to disease sites at much higher levels than traditional targeted nanoparticles.4 For example, this approach has harnessed immunity to deliver drugs to atherosclerotic plaques as a cardiovascular immunotherapy.5 In this issue, Chen et al.6 present an example of an innovative extension of the aforementioned targeting concept: creating nanoparticle hybrid ‘mimics’ of immune cells.7,8 By using membrane fragments from immune cells, which retain their surface proteins and evolutionarily honed targeting capabilities, and coating nanoparticles with these pieces of immune cell membrane, high-accumulation, precision drug targeting is enabled (Figure 1). Specifically, the authors borrowed targeting properties from the neutrophil, generating neutrophil-mimicking nanoparticles loaded with TAPI-1, a TACE/ADAM17 inhibitor. These drug-loaded, inflammation-targeted nanoparticles were thus developed to target inflamed myocardium in rats with myocardial infarction (MI). Neutrophils were selected as an attractive immune mimic given their rapid infiltration into infarcted hearts, allowing the nanoparticles to target the heart quickly and potentially mitigate cardiac dysfunction and adverse remodelling. The drug treatment helped protect the heart by reducing collagen deposition and fibrosis, with measurable functional effects after 4 weeks based on echocardiography demonstrating no reduction in left ventricular ejection fraction. Schematic outlining the Neu-LNP preparation procedure.6 The Chen et al. study offers a promising nanoparticle-based approach for targeted drug delivery in MI treatment. However, a major concern remains the off-target accumulation of neutrophil-derived lipid nanoparticles (Neu-LNPs) in organs such as the liver and spleen. The current study does not address whether such accumulation influences inflammation in these organs or whether off-target drug release could impact long-term toxicity. Indeed, eventual clinical translation will require extensive investigation into the long-term safety and pharmacokinetics of Neu-LNPs, particularly with respect to their off-target accumulation in the liver, spleen, and potentially bone marrow. Moreover, given the cell-based origins of these nanoparticles’ coatings, nanoparticle reproducibility and the feasibility of large-scale production will be critical milestones and regulatory challenges that must be addressed and overcome. Another potential issue is that the use of neutrophil-derived membranes raises questions about personalization: would each patient require nanoparticles derived from their own neutrophils, necessitating individualized (potentially very costly) production? Or could ‘off the shelf’ nanoparticles produced from allogeneic, engineered cells reliably grown in large bulk suffice? Future research will need to explore standardized production methods to ensure clinical feasibility. In summary, Chen et al.’s work represents a groundbreaking approach to targeted drug delivery in MI, leveraging immune cell ‘mimics’ to enhance accumulation and therapeutic precision. While the preclinical results are promising, future research must address off-target effects, long-term safety, therapeutic consistency, and production challenges. If Neu-LNPs prove effective and scalable, they could redefine treatment of MI, a leading cause of morbidity and mortality throughout the world.9 In the future, there are also exciting prospects that the use of an immune cell ‘mimic’—i.e. nanoparticles coated by selected immune cell membrane fragments—may be a generalizable paradigm to deliver therapeutic cargos. Such a platform could potentially enable delivery of other therapeutic agents including gene therapies and other novel therapeutics, specifically to diseased sites, such as ischaemic brain tissues, wounds, and even to solid tumours. Beyond gene therapies such as CRISPR-based gene editing or mRNA therapy, this approach could also facilitate the targeted accumulation of small molecules, biologics, and drugs in combination, enhancing their efficacy while helping to minimize systemic toxicity. Additionally, leveraging lipid, polymeric, or protein-based immune cell-mimic nanoparticles for the co-delivery and increased accumulation of immunomodulatory agents, such as monoclonal antibodies, small molecule immune agonists, or cytokines, may open new avenues for therapies including combination therapy in oncology, regenerative medicine, and cardiovascular disease. This article was supported by the Corewell-MSU Alliance Partnership and the National Institutes of Health (R01CA244491) to B.R.S. There are no new data associated with this article.
Source: Cardiovascular Research
DOI: 10.1093/cvr/cvaf050
Authors: Yapei Zhang, Charles C Hong, Bryan Ronain Smith
Institution: Michigan State University
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: bronze
OpenAlex ID: W4409213757