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 inter-system 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·, 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 CR-induced tumor theranostics.