Unveiling the multifaceted roles of extracellular vesicles in cancer: insights from molecular imaging and engineering strategies

Abstract

Extracellular vesicles (EVs), a class of nanoscale, membrane-bound vesicles secreted by various cell types, have emerged as rapidly advancing fields of research in recent years. This heterogeneous vesicle is a versatile carrier system for a variety of biomolecules, including proteins, nucleic acids, and metabolites. EVs play pivotal roles in intercellular communication, immune regulation, and disease pathogenesis, with particular implications for cancer biology. On the one hand, EVs promote tumor progression and metastasis by facilitating communication between cancer cells and their microenvironment. On the other hand, EVs carry noncoding RNAs, such as miRNAs and other regulatory RNAs, which directly modulate immune cell function or exert antitumor effects by influencing cancer cell proliferation and apoptosis. In addition to their biological roles, EVs show great potential as drug delivery systems because of their ability to be effectively taken up by target cells and stably deliver therapeutic payloads. In the context of cancer therapy, natural EVs demonstrate inherent therapeutic potential, particularly in targeting highly metabolically active organs. Furthermore, engineered EVs, which serve as both therapeutic vehicles and molecular imaging probes, have demonstrated significant potential for cancer theranostics. This review focuses on elucidating the dynamic changes and biological functions of EVs in vivo, with the aim of exploring the translational potential of EV-based molecular imaging and tracing technologies in cancer treatment. This work seeks to provide critical insights that may enhance the precision and efficacy of tumor therapies, offering a foundation for future clinical applications.

1. Introduction

Extracellular vesicles (EVs) represent a heterogeneous population of membrane-bound nanostructures that are actively secreted into various biological fluids. These evolutionarily conserved nanovesicles are ubiquitously produced by virtually all cell types and are naturally present in physiological fluids, including blood, saliva, urine, and breast milk. On the basis of their biogenesis pathways and size distribution, EVs can be classified into two primary schemes: size-based categorization and biogenesis-dependent subtyping. On the basis of their dimensional parameters, EVs can be broadly divided into small EVs (< 200 nm) and large EVs (> 200 nm). The biogenesis classification yields distinct subtypes, including exosomes (derived from multivesicular bodies), ectosomes (plasma membrane-derived), migrasomes (migration-dependent release), and apoptotic bodies (cell death-associated), among others [1]. In particular, small EVs, the smallest subtype characterized by their endosomal origin, serve as natural nanocarriers of diverse biomolecular cargo, including proteins, nucleic acids (e.g., mRNAs, microRNAs, lncRNAs, circRNAs), and metabolites. The intricate combination of these biomolecular components confers dual functionality to EVs, serving as both crucial biological messengers in cellular communication networks and efficient natural carriers for targeted therapeutic applications.

The biogenesis of EVs is initiated by invagination of the plasma membrane, which results in the formation of specialized microdomains that selectively incorporate extracellular components and membrane-associated molecules, thereby generating early endosomes. These early endosomes subsequently undergo a maturation process involving complex biochemical modifications and structural remodeling, ultimately transforming into multivesicular bodies (MVBs). During MVB formation, the limiting membrane of late endosomes buds inwardly, giving rise to intraluminal vesicles (ILVs) through a tightly regulated process. This crucial step is governed primarily by the endosomal sorting complex required for transport (ESCRT) machinery. The ESCRT system orchestrates the precise sorting and packaging of proteins, nucleic acids, and other biomolecules into ILVs, which constitute the fundamental cargo of future EVs. Notably, MVBs can undergo distinct trafficking fates: they may either fuse with the plasma membrane to release ILVs as EVs into the extracellular space or, alternatively, merge with lysosomes, leading to the degradation of their intraluminal contents through lysosomal enzymatic activity. This dual fate underscores the dynamic regulation of EV biogenesis and secretion (Figure 1).

This review focuses on the analysis of the dynamic changes in EVs in vivo and explores the application value of EV molecular imaging tracer technology in tumor treatment in detail, aiming to lay a foundation for providing more accurate information on the effects of tumor treatment and important information.