Engineering precision nanoparticles for drug delivery

Abstract

In recent years, the development of nanoparticles has expanded into a broad range of clinical applications. Nanoparticles have been developed to overcome the limitations of free therapeutics and navigate biological barriers - systemic, microenvironmental and cellular - that are heterogeneous across patient populations and diseases. Overcoming this patient heterogeneity has also been accomplished through precision therapeutics, in which personalized interventions have enhanced therapeutic efficacy. However, nanoparticle development continues to focus on optimizing delivery platforms with a one-size-fits-all solution. As lipid-based, polymeric and inorganic nanoparticles are engineered in increasingly specified ways, they can begin to be optimized for drug delivery in a more personalized manner, entering the era of precision medicine. In this Review, we discuss advanced nanoparticle designs utilized in both non-personalized and precision applications that could be applied to improve precision therapies. We focus on advances in nanoparticle design that overcome heterogeneous barriers to delivery, arguing that intelligent nanoparticle design can improve efficacy in general delivery applications while enabling tailored designs for precision applications, thereby ultimately improving patient outcome overall.

Fig. 1. Biological barriers to precision medicine applications.

Overview highlighting some of the biological barriers that nanoparticles (NPs) can overcome (inner ring) and precision medicine applications that may benefit from NPs (outer ring). As explored in this Review, intelligent NP designs that improve delivery have the potential to enhance the performance of precision medicines and, thus, accelerate their clinical translation. CAR, chimeric antigen receptor; EGFR, epidermal growth factor receptor; EPR, enhanced permeation and retention; gRNA, guide RNA; RNP, ribonucleoprotein.

Fig. 2. Classes of NPs.

Each class of nanoparticle (NP) features multiple subclasses, with some of the most common highlighted here. Each class has numerous broad advantages and disadvantages regarding cargo, delivery and patient response.

Fig. 3. NP characteristics impact distribution.

Factors such as size, shape, charge and surface coating determine what happens to nanoparticles (NPs) in the circulation, including clearance, and how the NPs interact with local barriers such as the tumour microenvironment or mucus layers. A few general trends are highlighted here: spherical and larger NPs marginate more easily during circulation, whereas rod-shaped NPs extravasate more readily (top left); and uncoated or positively charged NPs are cleared more quickly by macrophages (top right). In terms of local distribution, in general, rod-shaped, neutral and targeted NPs penetrate tumours more readily (bottom left) whereas positively charged, smaller and coated NPs more easily traverse mucosal barriers (bottom right).

Fig. 4. Common uptake pathways that ultimately determine NP fate within a cell.

a | Upon interaction with the cell surface, nanoparticles (NPs) — depending on their surface, size, shape and charge — are taken up by various types of endocytosis or pinocytosis via non-specific interactions, such as membrane wrapping, or specific interactions, such as with cell surface receptors. b | Once they have entered the cell, NPs remain trapped within vesicular compartments, or endosomes, that feature various characteristics such as internal or external receptors. To achieve functional delivery, most NPs must escape from these compartments before they acidify. Thus, responsive NPs — such as ionizable NPs that become charged in low-pH environments — aid in endosomal escape and allow for intracellular delivery whereas unresponsive NPs often remain trapped and are destroyed by lysosome acidity and proteolytic enzymes.

Fig. 5. Commonly engineered NP surface properties that allow for enhanced delivery.

Surface and material properties, architecture, targeting moieties and responsiveness are all attributes of nanoparticles (NPs) that can be altered in intelligent designs to tailor the platform to a specific application. Different combinations of these four properties allows for seemingly endless permutations of NP features and platforms. PEG, poly(ethylene glycol).