pH-driven butterfly effect for cascade-amplified tumor therapy based on thalidomide coordinated Fe-HMME nanoplatform

A promising approach for treating intractable cancers has been presented by photodynamic therapy (PDT). However, the limited penetration depth of PDT and suboptimal monotherapy efficacy of PDT significantly restrict its clinical applications. In this study, we constructed an acidic tumor microenvironment (TME)-activated carrier-free nanoplatform (HMME-Fe-Thal, abbreviated as HFT) through self-assembly of iron ions, photosensitizer hematoporphyrinmonomethyl ether (HMME) and anti-angiogenesis drug thalidomide (Thal). Near infrared (NIR) triggers PDT behavior before the degradation of the HFT nanoplatform. Subsequently, the HFT nanoplatform degrades, releasing Thal for chemotherapy, iron ions for chemodynamic therapy (CDT), which reinforce the therapeutic benefits of PDT synergistically. Moreover, the iron ions released by HFT degradation turn on the MRI signal, which can suggest the most appropriate time for PDT, divide the treatment into two stages (First-stage: PDT, Second-stage: CDT/chemotherapy), and gradually achieve cascade-amplified tumor therapy. In this sense, HFT modulates TME and leads to a "butterfly effect" of CDT/chemotherapy/glutathione (GSH) depletion for enhanced PDT efficacy. This strategy compensates the deficient shadow penetration and poor treatment efficacy from PDT monotherapy. This work presents the selection and rational design of HFT constructed by endogenous components for tumor regression, and greatly push nanomaterials towards the development of PDT application.