A versatile nano-transformer for efficient localization-specific imaging and synergistic therapy of bladder cancer

A stepwise morphologic transformation is highly desirable but rarely reported for promoting drug penetration at tumor sites via reducing transport barriers. Herein, an adhesive multifunctional nano-transformer (CTMF NPs) with cascading structural transformation was constructed, which afforded tumor microenvironment (TME)-activatable zero-background ¹⁹F-magnetic resonance imaging and ratiometric photoacoustic imaging-guided synergistic tumor therapy. CTMF NPs were synthesized via a one-pot encapsulation and dynamic coordination strategy, where copper sulfide nanoparticles (CuS NPs, photothermal agent) were co-encapsulated with perfluoro-15-crown-5-ether (PFCE, ¹⁹F MRI agent) by the dopamine grafted amphiphilic polymer, followed by coating with metal (Mn²⁺)-polyphenol shell (¹⁹F signal quencher and therapeutic agent). Benefiting from polyphenol enhanced cell adherence as well as in situ generated reactive quinone, the CTMF NPs attached to tumor sites and exhibited efficient internalization under TME promoted decomposition and oxidation. Moreover, these nano-platforms were further decomposed under laser irradiation, which amplified cellular oxidative stress, leading to mitochondrial structural damage and dysfunction, as well as facilitating cuproptosis by interfering with the lipoylated tricarboxylic acid cycle. Cell apoptosis subsequently resulted in significant immunogenic cell death and afforded a versatile nano-transformer for precise imaging-guided bladder cancer therapy.