Immunoisolation of pancreatic islets in alginate-based microcapsules is a promising approach for grafting of islets in absence of immunosuppression. However, loss and damage to the extracellular matrix (ECM) during islet isolation enhance susceptibility of islets for inflammatory stress. In this study, a combined strategy was applied to reduce this stress by incorporating ECM components (collagen type IV/RGD) and necroptosis inhibitor, necrostatin-1 (Nec-1) in alginate-based microcapsules in vitro. To demonstrate efficacy, viability and function of MIN6 β-cells and human islets in capsules with collagen type IV/RGD and/or Nec-1 was investigated in presence and absence of IL-1β, IFN-γ and TNF-α. The combination of collagen type IV/RGD and Nec-1 had higher protective effects than the molecules alone. Presence of collagen type IV/RGD and Nec-1 in the intracapsular environment reduced cytokine-induced overproduction of free radical species and unfavorable shifts in mitochondrial dynamics. In addition, the ECM components collagen type IV/RGD prevented a cytokine induced suppression of the FAK/Akt pathway. Our data indicate that the inclusion of collagen type IV/RGD and Nec-1 in the intracapsular environment prevents islet-cell loss when exposed to inflammatory stress, which might contribute to higher survival of β-cells in the immediate period after transplantation. This approach of inclusion of stress reducing agents in the intracapsular environment of immunoisolating devices may be an effective way to enhance the longevity of encapsulated islet grafts. Statement of significance: Islet-cells in immunoisolated alginate-based microcapsules are very susceptible to inflammatory stress which impacts long-term survival of islet grafts. Here we show that incorporation of ECM components (collagen type IV/RGD) and necrostatin-1 (Nec-1) in the intracapsular environment of alginate-based capsules attenuates this susceptibility and promotes islet-cell survival. This effect induced by collagen type IV/RGD and Nec-1 was probably due to lowering free radical production, preventing mitochondrial dysfunction and by maintaining ECM/integrin/FAK/Akt signaling and Nec-1/RIP1/RIP3 signaling. Our study provides an effective strategy to extend longevity of islet grafts which might be of great potential for future clinical application of immunoisolated cells.