Microscale devices are increasingly being developed for diagnostic analysis although conventional lysis as an initial step presents limitations due to its scale or complexity. Here, we detail the physical response of erythrocytes to the surface nanoarchitecture of black Si (bSi) and foreshadow their potential in microanalysis. The physical interaction brought about by the spatial convergence of the two topologies: (a) the nanopillar array present on the bSi and (b) the erythrocyte cytoskeleton present on the red blood cells (RBCs), provides spontaneous stress-induced cell deformation, rupture and passive lysis within an elapsed time of ∼3 min from immobilisation to rupture and without external chemical or mechanical intervention. The mechano-responsive bSi surface provides highly active yet autogenous RBC lysis and a prospect as a front-end platform technology in evolving micro-fluidic platforms for cellular analyses.