Genome release is a crucial step in the life cycle of picornaviruses. During virus intracellular transport in endosomes, exposure to low pH triggers a conformational change in the capsid necessary for genome release. As a result, some viruses form pores on symmetry axes, which have been proposed to facilitate slow release of the viral genome. In contrast, recent cryo-EM images have shown that viral capsids can crack open and release the genome rapidly. Thus, the mechanism of genome release remains elusive. We combined in vitro cryo-EM observations of the genome release from four viruses with coarse-grained simulations of generic virus-like nanoparticles to investigate the release pathways and virion stability. Here we show how the nature of interactions between capsid building blocks determines virion stability and genome release pathway. We found that preformed pores at the symmetry axes were not necessary for slow genome release. Rather, slow release occurred through transient pores when interactions between capsid subunits were long-range, and the interactions within the genome were weak. In contrast, rapid release was preferred when capsid interactions were short-range and/or the genome interactions were strong. These findings elucidate the genome release behavior of viruses and suggest a design strategy for virus-like nanoparticles for drug delivery.