Concepts of nanoparticle cellular uptake, intracellular trafficking, and kinetics in nanomedicine

Abstract

Nanoparticle-based therapeutics and diagnostics are commonly referred to as nanomedicine and may significantly impact the future of healthcare. However, the clinical translation of these technologies is challenging. One of these challenges is the efficient delivery of nanoparticles to specific cell populations and subcellular targets in the body to elicit desired biological and therapeutic responses. It is critical for researchers to understand the fundamental concepts of how nanoparticles interact with biological systems to predict and control in vivo nanoparticle transport for improved clinical benefit. In this overview article, we review and discuss cellular internalization pathways, summarize the field`s understanding of how nanoparticle physicochemical properties affect cellular interactions, and explore and discuss intracellular nanoparticle trafficking and kinetics. Our overview may provide a valuable resource for researchers and may inspire new studies to expand our current understanding of nanotechnology-biology interactions at cellular and subcellular levels with the goal to improve clinical translation of nanomedicines.

Introduction

The design and medical application of nanoparticles for diagnosis and treatment of diseases represent an important area of current nanotechnology research. This research field has been widely referred to as nanomedicine [1]. In nanomedicine, researchers engineer nanoparticles, for example, as delivery vehicles for therapeutics or imaging agents with the ultimate goal to improve clinical outcomes [2]. To achieve this goal, researchers need to be able to efficiently deliver nanoparticles to diseased sites in the body with cellular specificity and oftentimes subcellular precision [3]. Such efficient and effective nanomedicine delivery requires full control over the nanoparticle transport in the body. However, this level of control has not been achieved yet and is one of the greatest challenges in nanomedicine research [4].

Addressing this challenge is a major quest in the field which emphasizes the need to better understand the fundamental concepts of how nanoparticles interact with biological systems [5]. These nanotechnology-biology (i.e., nano-bio) interactions are complex, dynamic, and multiparametric, which poses substantial obstacles for the engineering of effective nanomedicines [6]. Factors that contribute to this complexity are manifold and include: (i) a nanoparticle’s physicochemical properties, including size, shape, surface chemistry, composition, architecture, density, and modulus; (ii) the biological and biochemical environments, including type of organ/tissue, biomolecular milieu and composition, pH, and other biochemical factors; and (iii) the interplay and interactions between these individual nanoparticle properties and biological/biochemical parameters, including the kinetics of nano-bio interactions [7].

While researchers are able to synthesize colloidal nanoparticles in the laboratory with precise physicochemical properties and functions, these deliberately designed nanoparticle characteristics may change substantially upon introduction of nanoparticles into a biological environment [8,9]. This phenomenon can be observed, for example, when nanoparticles are administered into the body through intravenous injection. Upon contact with blood, serum proteins adsorb non-specifically onto the nanoparticle surface to form a so-called protein corona [10,11]. The protein corona alters nanoparticles’ physicochemical properties by providing them with an unintentional biological identity [12]. Ultimately, this biological identity determines a nanoparticle’s interactions with biological systems, including organs, tissues, cells, and subcellular organelles [[13], [14], [15], [16]]. Therefore, nanoparticle in vivo transport and biodistribution are largely controlled by this biological identity rather than the deliberately engineered synthetic nanoparticle characteristics [17,18].

The fact that a nanoparticle’s physicochemical properties may change significantly upon biological exposure imposes major challenges for the engineering of nanomedicines. To advance our current understanding and to develop fundamental concepts needed for the design of more effective nanomedicines, researchers have started to describe and decipher essential mechanisms of how nanoparticles interact with biological systems. These studies can be divided into three categories: (i) nanoparticle interactions at organ and tissue levels; (ii) nanoparticle interactions at cellular and subcellular levels; and (iii) nanoparticle interactions with biomolecules and biochemical parameters. We focus in our review article on the second category, i.e., cellular and subcellular interactions of nanoparticles, and refer interested readers to excellent overview articles and original papers that cover nano-bio interactions at organ, tissue, and biomolecular levels [11,[19], [20], [21], [22], [23], [24], [25]].

To maximize clinical benefits of nanomedicines while minimizing side effects, researchers require profound understanding of nanoparticles’ cellular and subcellular interactions [19]. An intriguing example is the engineering of nanoparticles that are able to distinguish between healthy and diseased cells through the use of precise biomolecular recognition strategies [26,27]. To achieve this level of cellular identification and discrimination, a nanoparticle surface can be decorated with specific biomolecular ligands that can recognize and bind to complementary cell surface receptors on targeted cells [28]. The idea behind this concept is that upon recognition nanoparticles may deliver their payloads (e.g., active pharmaceutical ingredients; APIs; and imaging agents) preferentially to diseased cells while leaving healthy cells mostly unaffected. As some types of nanoparticle payloads require delivery to specific intracellular targets for maximizing efficacy, it is critical for researchers to understand and explore nanoparticles’ cellular interactions, intracellular trafficking pathways, and corresponding kinetics to ensure targeted delivery [[29], [30], [31], [32], [33]].

In this review, we describe the field’s understanding of three distinct aspects of nanoparticle-cell interactions: (i) nanoparticle cellular uptake; (ii) nanoparticle intracellular trafficking; and (iii) underlying kinetics of these cellular and subcellular nano-bio interactions. We hope that our review of these important concepts provides a valuable resource to researchers in the nanomedicine field and inspires new research to further enrich our knowledge of cellular and subcellular nanoparticle interactions. With improved knowledge and understanding, better control over nanoparticle transport in the body may be achieved, which could ultimately result in improved clinical benefits of nanomedicines.