“One Rocket, Multiple Satellites”: Natural Small Molecule Nanocarriers With In‐Situ Nanosphere‐to‐Nanofiber Transition for Combined Chemo/PDT/Anti‐Angiogenic Antitumor Therapy

Drug delivery based on dynamic morphological transformation represents the cutting-edge strategy at the forefront of chemotherapy, integrating individual advantages that depend on the delivery stage and spatially resolved morphology. However, developing a tumor-specific, in vivo morphologically transformable small-molecule drug delivery system to achieve enhanced drug accumulation and photodynamic therapy (PDT) efficacy remains challenging. In this study, a multifunctional PDT formulation using natural small molecules as nanocarriers is developed, combining a tumor-targeting photosensitizer and anti-angiogenic therapy. After intravenous injection, it undergoes dramatic morphological and size changes from nanospheres (≈ 153 nm in diameter) to nanofibers (≈ 953 nm in length), enhancing the enrichment and retention of nanomaterials in the tumor area. Simultaneously, the release of the photosensitizer (Ce6) and anti-angiogenic drug (ORI) from the nanospheres produces a cascade effect to achieve amplified ¹O₂ generation capacity. Both in vitro and in vivo therapeutic results demonstrate that these nanoparticles exhibit significant antitumor efficacy through combined chemo/PDT/anti-angiogenic therapy. That the "smart" responsive concept employed in this work holds great significance for the future development of novel combination therapies for cancer and other diseases is predicted.