Transferrin (Tf) is known to induce transcytosis, which is a consecutive endocytosis/exocytosis event. We developed a Tf-appended nanocaplet ((NC)-N-Tf superset of siRNA) for the purpose of realizing siRNA delivery into deep tissues and RNA interference (RNAi) subsequently. For obtaining (Tf)NCDsiRNA, a macro monomer ((Az)Gu) bearing multiple guanidinium (Gut) ion units, azide (N-3) groups, and trityl (Trt)-protected thiol groups in the main chain, side chains, and termini, respectively, was newly designed. Because of a multivalent Gut phosphate salt-bridge interaction, (Az)Gu can adhere to siRNA along its strand. When 12 was added to a preincubated mixture of AzGu and siRNA, oxidative polymerization of (Az)Gu took place along the siRNA strand, affording C-AN superset of siRNA, the smallest siRNAcontaining reactive nanocaplet so far reported. This conjugate was converted into Glue/BPN superset of siRNA by the click reaction with a Gut-appended bioadhesive dendron (Glue) followed by a benzophenone derivative (BP). Then, Tf was covalently immobilized onto clue/spNc D_ siRNA by Gut-mediated adhesion followed by photochemical reaction with BP. With the help of Tf-induced transcytosis, TfNCDsiRNA permeated deeply into a cancer spheroid, a 3D tissue model, at a depth of up to nearly 70 jAm, unprecedentedly.