ARMMs and Their Potential in Cell-to-Cell Communication

Cells exchange information through various signaling mechanisms, ensuring coordinated responses in both normal physiology and disease states. Among these, extracellular vesicles (EVs) play a crucial role in transferring molecular cargo between cells. A recently identified class of EVs, arrestin domain-containing protein 1 (ARRDC1)-mediated microvesicles (ARMMs), provides a distinct mode of intercellular communication.

Understanding ARMMs is essential, as they influence diverse biological processes and hold promise for therapeutic applications. Researchers are investigating their formation, cargo, and impact on recipient cells to harness their potential for drug delivery and regenerative medicine.

Biogenesis Mechanisms

ARMM formation is a tightly regulated process that sets them apart from other extracellular vesicles. Unlike exosomes, which originate from the endosomal system, ARMMs bud directly from the plasma membrane. ARRDC1 plays a central role in recruiting cellular machinery for vesicle release. It interacts with components of the endosomal sorting complex required for transport (ESCRT), traditionally associated with membrane remodeling and vesicle trafficking. Engaging ESCRT proteins, ARRDC1 facilitates outward budding and detachment from the cell surface.

Lipid composition also influences ARMM biogenesis. Cholesterol- and sphingolipid-enriched membrane domains, known as lipid rafts, provide structural support for vesicle formation. These specialized regions concentrate ARRDC1, ensuring ARMMs maintain a distinct molecular identity. Post-translational modifications of ARRDC1, such as ubiquitination, further regulate its activity, fine-tuning vesicle release.

Cytoskeletal dynamics contribute to ARMM detachment. Actin remodeling, mediated by proteins like cofilin and cortactin, facilitates membrane curvature and scission. This process resembles viral budding, where host cell machinery enables particle release. VPS4, an ATPase, supplies the energy required for membrane fission, ensuring efficient vesicle separation. The interplay of these molecular components highlights the complexity of ARMM biogenesis.

Structure And Cargo

The molecular composition of ARMMs defines their function, distinguishing them from other extracellular vesicles. These vesicles encapsulate lipids, proteins, and RNA, ensuring cargo stability and targeted interactions with recipient cells.

Lipid Envelope

The lipid composition of ARMMs plays a key role in their stability and function. Enriched in cholesterol, sphingolipids, and phosphatidylserine, ARMM membranes maintain rigidity and resist degradation. Cholesterol enhances structural integrity, while lipid rafts serve as assembly sites for vesicle formation, ensuring selective incorporation of proteins and signaling molecules. Phosphatidylserine exposure on the vesicle membrane may facilitate interactions with recipient cells by engaging specific receptors. This lipid asymmetry sets ARMMs apart from exosomes, which exhibit a more uniform lipid distribution.

Protein Content

ARMMs carry a distinct set of proteins that contribute to their biological activity. A defining feature is the presence of ARRDC1, which orchestrates biogenesis and may influence cargo selection. Proteomic analyses have identified additional proteins, including ESCRT components, cytoskeletal regulators, and signaling molecules. ARMMs are enriched in ubiquitinated proteins, suggesting a role in protein quality control and targeted degradation. They also package functional transcription factors and signaling adaptors, which can modulate gene expression in recipient cells. This selective enrichment underscores ARMMs’ role as mediators of intercellular signaling.

RNA Load

Beyond proteins, ARMMs transport RNA molecules that influence gene expression in recipient cells. These vesicles contain messenger RNA (mRNA) and microRNA (miRNA), which can be transferred to target cells and modulate transcription. Unlike exosomes, which mainly carry small non-coding RNAs, ARMMs have been found to transport full-length mRNAs capable of translation. RNA-binding proteins likely govern RNA selection and packaging. This ability to deliver regulatory RNAs highlights ARMMs’ role in post-transcriptional gene regulation.

Distribution Across Cell Types

ARMMs are produced by a variety of cell types, reflecting their broad functional significance. Epithelial cells, found in the skin, lungs, and gastrointestinal tract, are prolific producers. Their ARMM release may facilitate local communication within tissue microenvironments, enabling coordinated responses to physiological changes.

Endothelial cells lining blood vessels also generate ARMMs, contributing to their presence in circulation. Unlike exosomes, which often function in localized signaling, ARMMs appear capable of traveling significant distances, potentially affecting distant target cells. Their composition may vary with physiological conditions, reflecting changes in vascular integrity.

Fibroblasts, which provide structural support in connective tissues, also release ARMMs. Their vesicle production appears more selective, potentially influencing cell proliferation and differentiation in response to mechanical stress or injury. Unlike epithelial and endothelial cells, which continuously shed vesicles, fibroblasts may regulate ARMM release based on functional demands.

Role In Cell-To-Cell Communication

ARMMs enable molecular exchange between cells through a unique mechanism. Their direct budding from the plasma membrane allows for selective cargo packaging and efficient delivery to recipient cells. Unlike exosomes, which require endocytic uptake and intracellular processing before releasing cargo, ARMMs can fuse with target cell membranes or engage surface receptors for immediate molecular transfer.

A key feature of ARMM-mediated signaling is the transfer of functional proteins and RNA species that directly influence recipient cells. Transcription factors packaged within ARMMs remain structurally intact and capable of modulating gene expression. This contrasts with other extracellular vesicles, which often rely on indirect pathways, such as endosomal escape. By delivering pre-formed regulatory molecules, ARMMs accelerate cellular responses to external cues, particularly in dynamic tissue environments requiring rapid adaptation.

Relevance To Biotherapeutic Development

ARMMs’ unique properties have sparked interest in their potential for biotherapeutics, particularly in drug delivery and gene therapy. Their ability to transfer bioactive molecules efficiently makes them promising candidates for delivering therapeutic proteins, nucleic acids, or small molecules to specific cell populations. Unlike synthetic nanoparticles, ARMMs are naturally biocompatible, reducing the risk of immunogenicity and enhancing circulation time. Their direct plasma membrane budding mechanism allows for selective cargo packaging, minimizing off-target effects.

One promising application is the delivery of functional RNA molecules for gene regulation. ARMMs’ ability to transport full-length mRNAs distinguishes them from exosomes, which primarily carry fragmented or non-coding RNA species. This suggests ARMMs could introduce therapeutic transcripts into diseased cells, enabling endogenous protein production without viral vectors. Their capacity to shuttle transcription factors and regulatory proteins also suggests a role in cellular reprogramming, valuable for regenerative medicine. Researchers are exploring engineered ARMMs with customized cargo to enhance therapeutic efficacy, including targeting moieties for specific tissues. Optimizing ARMM production and scalability will be crucial for translating these findings into clinical applications.