The discovery of safe platforms that can circumvent the endocytic pathway is of great significance for biological therapeutics that are usually degraded during endocytosis. Here we show that self-assembled and dynamic macrocycles can passively diffuse through the cell membrane and deliver a broad range of biologics including proteins, CRISPR Cas9 and ssDNA directly to the cytosol while retaining their bioactivity. Cell penetrating macrocycles (CPMs) can be easily prepared from the room temperature condensation of diketopyrrolopyrrole lactams with diamines. We attribute the high cellular permeability of CPMs to their amphiphilic nature and chameleonic properties. They adopt conformations that partially bury polar groups and expose hydrophobic side chains thus self-assembling into micellar-like structures. Their superior fluorescence renders CPMs trackable inside cells where they follow the endomembrane system. CPMs outperformed commercial reagents for biologics delivery and showed high RNA knockdown efficiency of CRISPR Cas9. We envisage that this class of macrocycles will be an ideal starting point to design and synthesize biomimetic macrocyclic tags that can readily facilitate the interaction and uptake of biomolecules and overcome endosomal digestion.