The quality-failure paradox in extracellular vesicle therapeutics: quantitative benchmarking of 152 clinical trials against CAR-T cell therapies.

The stall in clinical translation of extracellular vesicle (EV) therapeutics requires addressing critical and hidden causes of attrition and delays. Despite more than 150 registered clinical trials and fifteen years of clinical investigation, small EV (sEV) therapeutics have yielded zero FDA approvals, a translational deficit that has received remarkably little quantitative scrutiny. We systematically evaluated 783 EV-related clinical trials (152 of which therapeutic) registered through December 2025, benchmarking the sEV pipeline against 1,131 CAR-T cell therapy trials (ex-China) that share the "process is the product" manufacturing constraint, yet have delivered six FDA-approved products. A quality-failure paradox emerges, in which industry-sponsored sEV trials exhibit 39% higher composite methodological quality (quality index 2.49 vs. 1.79) yet fail at approximately five-fold the rate of academic programmes (28.6% vs. 5.1%; OR=7.40, 95% CI 2.5-22.3, p=0.0004). Cross-modality replication in CAR-T trials confirms the direction of this association (OR=2.51, p<0.001; Cochran-Mantel-Haenszel pooled OR=2.76, p<0.001). Registry abandonment, affecting 24% of academic sEV trials, constitutes a hidden failure mode that, when reclassified, dissolves the apparent paradox. Premature clinical entry of incompletely defined products, rather than insufficient methodological rigour, represents the central constraint on sEV translational progress. The opacity of research data, inadequate clinical evaluation, and failure to report negative (null) findings in clinical trials create a hidden crisis that drains hundreds of millions invested by public and private sector-eroding the return on investment-and traps progress in cycles of duplicated effort, wasteful resource allocation, and missed learning opportunities.