A sequential dual-locked strategy with pH-responsive activation of photosensitizers and precise Cerenkov radiation delivery for cancer theranostics

Cerenkov radiation (CR)-induced therapy (CRIT) has emerged as a promising modality to overcome the limitation of light penetration in conventional photodynamic therapy (PDT). Nevertheless, achieving a balance between efficacy and safety of CRIT remains a significant challenge. Here, we propose a dual-locked strategy that sequentially delivers a pH-activatable photosensitizer, bovine serum albumin (BSA)-packed chlorin e6 (Ce6) and MnO2 nanodots (BCM), and 68Ga-labeled CD47-targeting C2 nanobody (68Ga-C2) for safe and effective CRIT in tumors. BCM serves as both a tumor microenvironment (TME) modulator and a pH-activatable photosensitizer, which exhibits minimal phototoxicity in normal tissues due to its quenched fluorescence and attenuated intersystem crossing (ISC) induced by MnO2 nanodots. Upon exposure to the acidic TME, BCM unlocks its bifunctionality, triggering a self-cascade catalysis reaction to supply O2 and cytotoxic HO & sdot;, while simultaneously depleting GSH. Cerenkov radiation from 68Ga-C2, subsequently delivered, illuminates the activated Ce6 molecules in BCM, inducing a burst generation of singlet oxygen, which is further enhanced by the pre-modulated TME. The acidic TME and tumor-targeting 68Ga-C2 provide two keys to ensure a selective reactive oxygen species (ROS) burst in the tumor sites while minimizing ROS generation in normal tissues. This pH-activatable CRIT induces DNA damage and mitochondrial dysfunction of tumor cells, effectively suppressing tumor growth with minimal side effects on CD47-expressing LS174T tumor models. This study highlights the potential of using pH-activatable photosensitizers in cancer therapy and provides a reference for future research in CRinduced tumor theranostics.

Automated summary

This study proposes a dual-locked strategy for safe and effective Cerenkov radiation-induced therapy (CRIT), using pH-activatable photosensitizers. The strategy shows promising results in tumor models, highlighting the potential of pH-activatable photosensitizers in cancer therapy.