Strict criteria of biomedical materials in synthesis efficiency, structure determinacy, and biological safety pose formidable challenges for the synthesis of dobby polypeptides. Herein we reported a cyclodextrin (CD)-initiated, 1,1,3,3-Tetramethylguanidine (TMG)-catalyzed one-step N-carboxyanhydride (NCA) ring-opening polymerization (ROP) strategy to synthesize a series of dobby polypeptides that fulfill the criteria of biomedical materials. By leveraging TMG's catalytic mechanisms in nucleophilicity enhancement for CD hydroxyl groups and active center creation for NCA monomers, this strategy achieves efficient NCA polymerization within 2 hours and high monomer conversion up to 93.5%. Meticulous characterizations illustrate that CD-centric polypeptides present jellyfish-type stereochemical structures, in which the arm number, length, orientation and initiation sites are precisely determined. Simultaneously, CD-centric polypeptides possess excellent self-assembling capacities to guide nanostructure fabrication, exhibiting broad-spectrum small-molecule drug encapsulation. Additionally, natural CD applied in multipoint initiation of core-first NCA ROP fundamentally improves the biodegradability and biosafety of dobby polypeptides, thus facilitating their biomedical applications.