The precise and highly efficient drug delivery of nanomedicines into lesions remains a critical challenge in clinical translational research. Here, an autocatalytic morphology transformation platform is presented for improving the tumor-specific accumulation of drugs by kinetic control. The in situ reorganization of prodrug from nanoparticle to β-sheet fibrous structures for targeted accumulation is based on nucleation-based growth kinetics. During multiple administrations, the autocatalytic morphology transformation can be realized for skipping slow nucleating process and constructing the bulky nanoassembly instantaneously, which has been demonstrated to induce the cumulative effect of prodrug. Furthermore, the sustained drug release from fibrous prodrug depot in the tumor site inhibits the tumor growth efficiently. The autocatalytic morphology transformation strategy in vivo offers a novel perspective for targeted delivery strategy by introducing chemical kinetics and shows great potential in disease theranostics.