Gomez Cid, LidiaLópez-Donaire, María LuisaVelasco Bayón, DiegoMarín Calahorrano, Víctor-JesúsGonzález, María IsabelSalinas Rodríguez, BeatrizCusso Mula, LorenaGarcía, ÁngelBravo, Susana BelénFernández-Santos, María EugeniaElvira, CarlosSierra, JohannaArroba, EsterBañares, RafaelGrigorian-Shamagian, LilianFernández-Avilés, Francisco2021-09-302021-09-302021-09-01International Journal of Molecular Sciences, 22(17), 9226.1422-0067https://hdl.handle.net/10016/33348This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0Stem-cell-derived extracellular vesicles (EVs) have demonstrated multiple beneficial effects in preclinical models of cardiac diseases. However, poor retention at the target site may limit their therapeutic efficacy. Cardiac extracellular matrix hydrogels (cECMH) seem promising as drug-delivery materials and could improve the retention of EVs, but may be limited by their long gelation time and soft mechanical properties. Our objective was to develop and characterize an optimized product combining cECMH, polyethylene glycol (PEG), and EVs (EVs–PEG–cECMH) in an attempt to overcome their individual limitations: long gelation time of the cECMH and poor retention of the EVs. The new combined product presented improved physicochemical properties (60% reduction in half gelation time, p < 0.001, and threefold increase in storage modulus, p < 0.01, vs. cECMH alone), while preserving injectability and biodegradability. It also maintained in vitro bioactivity of its individual components (55% reduction in cellular senescence vs. serum-free medium, p < 0.001, similar to EVs and cECMH alone) and increased on-site retention in vivo (fourfold increase vs. EVs alone, p < 0.05). In conclusion, the combination of EVs–PEG–cECMH is a potential multipronged product with improved gelation time and mechanical properties, increased on-site retention, and maintained bioactivity that, all together, may translate into boosted therapeutic efficacy.18eng© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.Atribución 3.0 EspañaExtracellular vesiclesHydrogelExtracellular matrixDrug deliveryPolyethylene glycolCardiac regenerative therapyresearch articleBiología y Biomedicinahttps://doi.org/10.3390/ijms22179226open access922617International Journal of Molecular Sciences22AR/0000028401