We report on the encapsulation of high loadings of liquid isophorone diisocyanate (IPDI) in biodegradable, temperature-responsive poly(ε-caprolactone) (PCL) microcapsules (MCs), aimed to be applied as cross-linking agents for the development of a generation of safer and eco-innovative adhesives, which are one-component and self-reactive. The biodegradable PCL MCs were formed via the solvent evaporation method in combination with an oil-in-oil-in-water (O/O/W) doubleemulsion system. Two PCL grades with different molecular weights (MW), of 45000 and 80000 Da, were tested as the MCs' outer surface (shell) material. The use of a higher MW PCL, for the encapsulation of IPDI, resulted in core−shell MCs of smoother surface and a slightly smaller average shell thickness leading to remarkably high isocyanate loadings, up to 60 wt %. Also, a higher resistance of the MC's shell to air moisture diffusion was revealed by the longer shelf life exhibited by these MCs. The successful IPDI encapsulation and MCs' shell composition were revealed by Fourier transform infrared spectroscopy (FTIR) in combination with thermogravimetric analysis (TGA) and gel permeation chromatography (GPC), while the MCs' morphology and size distribution were assessed by scanning electron microscopy (SEM) and optical microscopy. Differential scanning calorimetry (DSC) in combination with adhesion proof-of-concept studies showed that the developed PCL MCs were able to respond to the external stimuli of temperature and pressure, typically employed during the adhesive application, revealing an effective IPDI release in the adhesive joint. The results obtained confirm the viability of the sustainably engineered MCs to be used as cross-linking agents and therefore enablers of eco-innovative high-performance adhesives. Finally, it should be stressed that the obtained MCs are potentially useful to provide self-healing capability to materials and that the developed technology may be used in the encapsulation of other reactive species by means of a purely physical process using biodegradable polymers.