A chloroplast-inspired nanoplatform for targeting cancer and synergistic photodynamic/photothermal therapy

Specific targeting capabilities and effective phototherapeutic functions are the key demands for precise cancer phototherapeutic agents. Herein, a bioinspired nanoplatform composed of Cu(II)-chlorophyll–hyaluronic acid nanoparticles (Cu(II)Chl–HA NPs) was developed for targeting cancer and synergistic photodynamic/photothermal therapy. Inspired by the photonic biosystem of the chloroplast, Cu(II) chlorophyll was used as a photosensitive substituent to covalently connect with a hydrophilic HA tail rather than a natural phytol tail, and this conjugate further assembled into a nanoparticle-like morphology under non-covalent interaction. Time-dependent density functional theory calculations reveal that the Cu(II) chlorophyll has a much smaller energy gap between an excited singlet and excited triplet, and theoretically leads to rapid electron intersystem crossing that would benefit the PDT effect. In addition, a series of experiments have proven that, under 650 nm laser irradiation, the nanoplatform of Cu(II)Chl–HA can produce a high amount of singlet oxygen and exhibit an outstanding photothermal conversion capability. More interestingly, owing to the specific interactions between the HA component and the CD44 receptor on the cell membrane, the HA tails impart Cu(II)Chl–HA NPs an excellent receptor-mediated targeting performance toward CD44-overexpressing cancer cells. Based on these features, the nanoplatform of Cu(II)Chl–HA NPs presents active targeting and outstanding dual modality synergistic PDT/PTT performance of cancer both in vitro and in vivo. Thus, this work opens up a new strategy to fabricate a bioinspired multifunctional cancer phototherapy nanoplatform.