Engineered extracellular vesicles could move beyond cargo delivery to reshape diseased tissue microenvironments

Extracellular vesicles (EVs) are increasingly being explored as biological delivery vehicles because they naturally transport proteins, lipids and nucleic acids between cells. Published on EXO - Beyond the Cell, the review is led by Prof. Ye Chen of Zhejiang University and examines how advances in EV engineering may expand their therapeutic role beyond delivering cargo to individual cells toward the coordinated remodeling of diseased tissue microenvironments.

Traditionally, EV-based therapies have largely been conceptualized as a targeted delivery process: load a therapeutic molecule into an EV, deliver it to a recipient cell, and alter that cell’s behavior. The authors propose a broader framework of “niche remodeling,” in which engineered EVs influence multiple cellular or extracellular components within a local tissue environment and ultimately produce a measurable tissue-level functional outcome.

Achieving this transition requires overcoming several biological barriers. The review discusses strategies to improve cargo loading by harnessing EV biogenesis machinery or using active loading approaches. For mRNA delivery, however, successful loading does not guarantee therapeutic activity: after cellular uptake, cargo may remain trapped in endosomal compartments rather than reaching the cytoplasm for translation, making efficient endosomal escape a critical step. Surface engineering can further influence EV interactions with selected tissues or cell types, although increased target-tissue uptake does not necessarily translate into highly specific targeting because whole-body biodistribution and off-target uptake remain important considerations.

The review also highlights biomaterial-assisted delivery as a complementary strategy for controlling the localization and duration of EV activity. Hydrogels, microneedles and stimulus-responsive systems can improve local retention and regulate EV release, potentially providing the spatial and temporal control needed to influence a tissue niche rather than producing only a transient cellular response.

Across oncology, regenerative medicine and neurological disease, emerging preclinical studies illustrate the potential of this approach. In cancer, for example, EVs carrying immunomodulatory mRNAs have been investigated for locally reprogramming the tumor immune microenvironment, including studies using IL-12 mRNA-loaded EVs that associated localized IL-12 expression with immune activation and reduced tumor growth in preclinical models. In regenerative medicine, EVs integrated with biomaterial scaffolds have been explored to support neovascularization, tissue repair and extracellular matrix remodeling. In neurological disease, engineered EVs have been investigated for improving delivery across the blood–brain barrier and modulating neuroinflammation and disease-associated microenvironments.

Despite these advances, engineered EVs remain an emerging therapeutic platform. Scalable manufacturing, EV heterogeneity, batch-to-batch reproducibility, product standardization and robust potency assays remain important challenges for clinical translation. Better manufacturing and characterization strategies, together with functional assays linking EV properties to biological activity, will be essential for advancing these platforms beyond preclinical development.

Overall, the review presents engineered EVs not as an established clinical solution, but as an evolving therapeutic strategy that could move the field from delivering cargo to individual cells toward coordinated remodeling of pathological tissue niches. Continued advances in EV engineering, biomaterials, manufacturing and functional characterization will determine how far this emerging concept can translate into therapies for complex diseases.