The
increased risk of breast cancer metastasis is closely linked
to the effects of platelets. Our previously light-switchable diphtheria
toxin A fragment (DTA) gene system, known as the LightOn system, has
demonstrated significant therapeutic potential; it lacks antimetastatic
capabilities. In this study, we devised an innovative system by combining
cell membrane fusion liposomes (CML) loaded with the light-switchable
transgene DTA (pDTA) and a ticagrelor (Tig) prodrug. This innovative
system, named the sequential rocket-mode bioactivating drug delivery
system (pDTA-Tig@CML), aims to achieve targeted pDTA delivery while
concurrently inhibiting platelet activity through the sequential release
of Tig triggered by reactive oxygen species with the tumor microenvironment.
In vitro investigations have indicated that pDTA-Tig@CML, with its
ability to sequentially release Tig and pDTA, effectively suppresses
platelet activity, resulting in improved therapeutic outcomes and
the mitigation of platelet driven metastasis in breast cancer. Furthermore,
pDTA-Tig@CML exhibits enhanced tumor aggregation and successfully
restrains tumor growth and metastasis. It also reduces the levels
of ADP, ATP, TGF-β, and P-selectin both in vitro and in vivo,
underscoring the advantages of combining the bioactivating Tig prodrug
nanoplatform with the LightOn system. Consequently, pDTA-Tig@CML emerges
as a promising light-switchable DTA transgene system, offering a novel
bioactivating prodrug platform for breast cancer treatment.