ApoBDs: a paradigm shift from cellular debris to therapeutic vehicles

Abstract

Apoptosis, a genetically programmed cell death process, is essential for maintaining tissue homeostasis. Apoptotic vesicles (ApoVs), membrane-bound vesicles generated during apoptosis and once considered mere cellular debris, can be classified into apoptotic bodies (ApoBDs), microvesicles, and apoptotic extracellular vesicles (ApoEVs) based on their grain size. These vesicles, packed with bioactive molecules, not only drive tumor growth and metastasis, but also contribute to tissue and organ repair. This review focus on the origins, formation mechanisms, and dual functions of ApoBDs across various diseases, highlighting their paradoxical nature as both disease promoters and therapeutic allies. It further explores the application prospects and clinical practice of ApoBDs in cancer treatment, immune modulation, and tissue regeneration. Additionally, we provide a comprehensive perspective on the transformative potential of ApoBDs in modern medicine, while outlining current challenges and future directions for ongoing research and clinical application.

Keywords: apoptotic bodies; apoptotic vesicles; diagnosis; therapeutics; tissue regeneration.

Figure 1

The process of cell apoptosis. There are two principal apoptotic pathways. The intrinsic pathway: cells respond to stress by prompting Bax/Bak oligomerization and mitochondrial outer membrane permeabilization and the release of factors such as cytochrome c. These factors facilitate assembly of the Apaf-1-caspase-9-apoptosome, leading to caspase-3/7 activation. The extrinsic pathway: it is initiated by ligand binding to death receptors (e.g., FAS) of the TNF receptor superfamily, which recruits FADD and triggers formation of the death-inducing signaling complex (DISC), activation of initiator caspases-8 and -10, and subsequent activation of caspase-3/7 to drive apoptosis.

Figure 2

The generation of ApoBDs. The disassembly of apoptotic cells into ApoBDs occurs in three sequential stages. First, executioner caspase-3/7 activation of ROCK1, together with PLA₂-mediated alterations in transmembrane pressure, drives rapid cell shrinkage and the formation of spherical membrane blebs on the apoptotic cell surface. Second, it involves apoptotic membrane protrusions. Different apoptotic cells exhibit distinct membrane deformation patterns, such as membrane blebbing, others manifest microtubule-driven spikes or beaded apoptotic structures. Third, apoptotic cells undergo fragmentation: ESCRT-III complex–mediated neck constriction of membrane protrusions results in scission and release of vesicles containing organelles and nuclear fragments, which mature into ApoBDs.

Figure 3

Mechanisms of ApoBDs action in diseases. ApoBDs carry various cargos such as miRNA, DNA, and proteins, which regulate the phenotype of target cells through the aforementioned pathways or synergistic mechanisms, thereby influencing disease progression or tissue repair.

Figure 4

Therapeutic and reparative potential of ApoBDs in disease contexts. Apoptotic bodies exhibit multiple functions in the progression of diseases: they possess both pro-tumorigenic and anti-tumorigenic properties, exert dual regulatory effects during fibrosis, and play a critical role in tissue and organ repair. This figure was created by Figdraw.