Cancer Photodynamic Therapy Enabled by Water-Soluble Chlorophyll Protein

Photodynamic therapy (PDT) has been utilized to treat various malignant cancers for more than a century. However, many photosensitizers (e.g., derivatives of porphyrins, chlorins, etc.) central to PDT are still suffering from limitations such as water insolubility, dark toxicity, photo/thermal-instability, difficult synthesis/preparation, and poor tumor selectivity. Numerous effective strategies include designing new synthetic photosensitizers by exploiting heavy atom effect, aggregation-induced emission effect (AIE), and electronic/energy effects (donor-acceptor, and Förster resonance energy transfer: FRET), and the linkage of activatable and targeting molecules has been developed to address one or more of these limitations. However, these structural modifications of photosensitizing organic molecules are synthetically challenging and unpredictable in terms of efficacy versus toxicity. Herein, we report a new and simple strategy for effective PDT by combining natural spinach-derived chlorophylls (photosensitizer) with natural water-soluble chlorophyll proteins (WSCPs) derived originally from plants and produced heterologously by bacteria (<i>E. coli</i>). The recombinant WSCPs (chlorophyll-WSCP) are tetrameric and stable under air/thermal conditions and importantly can produce highly reactive singlet oxygen under red/far-red light irradiation to induce cancer cell death. Our in vivo mouse model studies (melanoma xenografts) further validate the efficacy of the recombinant WSCPs as a new class of water-soluble, nontoxic, and highly efficient photosensitizers for PDT. This work represents the first example of the application of WSCPs in PDT and may advance the clinical applications of PDT for cancer treatment.