Redefining long-acting injectables: the emerging role of extracellular vesicles in sustained drug delivery.

Long-acting drug delivery systems (LADDS) have emerged as an effective strategy to overcome the limitations of conventional oral and parenteral therapies, enabling sustained drug exposure, reduced dosing frequency, and improved patient compliance. To date, clinically approved long-acting injectables (LAIs) predominantly rely on chemical platforms, including biodegradable polymeric depots, lipid-based formulations, and crystalline nanosuspensions. Although these systems have demonstrated significant clinical success, their performance is largely dictated by formulation-dependent physicochemical mechanisms and is often associated with challenges such as local tissue reactions, formulation instability, and limited flexibility in controlling release kinetics. In recent years, biologically derived carriers have gained increasing attention as next-generation long-acting delivery systems. Among these, extracellular vesicles (EVs) represent a unique class of endogenous nanocarriers with intrinsic stability, low immunogenicity and biologically driven interactions with tissues and cells, thereby positioning them as promising candidates for sustained drug delivery applications. This review summarizes current LAI technologies, highlighting the strengths and limitations of established chemical LAIs, and critically examines the emerging potential of EV-based injectable systems. Particular emphasis is placed on engineering strategies that enable EVs to acquire depot-like behavior, including hydrogel-based formulations and microneedle platforms that extend local retention and modulate release kinetics while preserving EV bioactivity. Finally, key challenges related to manufacturing scalability, reproducibility, regulatory standardization, and clinical translation of EV-based LAIs are discussed. This review outlines the opportunities and remaining barriers for translating EVs into clinically viable long-acting drug delivery applications. Overall, these considerations provide a framework for advancing the rational design and clinical translation of EV-based long-acting delivery platforms.