Tumor microenvironment activated nanoreactors for chemiluminescence imaging-guided simultaneous elimination of breast tumors and tumor-resident intracellular pathogens

• Exogenous H 2 O 2 was introduced to realize self-reinforcing CDT and chemiexcited PDT; • The multifunctional chemiluminescence nanoreactor eliminated breast tumors and tumor-resident intracellular pathogens simultaneously; • Self-reinforcing chemiluminescence imaging was used to guide tumor therapy. Tumor-resident intracellular pathogens seriously cause tumor metastasis, recurrence, and drug resistance. However, the development of multifunctional platforms for effectively simultaneous elimination of tumors and tumor-resident intracellular pathogens remains challenging. Here, a novel tumor microenvironment (TME) activated self-reinforcing chemiluminescence (CL) nanosystem with chemiexcited emission, singlet oxygen ( 1 O 2 ), and hydroxyl radicals (·OH) generation is reported for simultaneous elimination of tumors and intracellular pathogens in cancer cells. Bis[3,4,6-trichloro-2-(pentyloxycarbonyl) phenyl] oxalate (CPPO), chlorin e6 (Ce6) and copper peroxide nanodots (CuO 2 NDs) were co-encapsulated by poly (D, L-lactide-co-glycolide) (PLGA) based on oil-in-water (O/W) emulsion method to form chemiluminescence nanocapsules (CPPO/Ce6/CuO 2 @PLGA) with cascade nanoenzyme activity. Once in cells, the loaded CuO 2 NDs dissociated under acidic TME, releasing both Cu 2+ with glutathione depletion and Fenton catalysis and H 2 O 2 for chemodynamic therapy through a Fenton-like reaction. Meanwhile, the sufficient chemical energy generated by the reaction between H 2 O 2 and CPPO activates Ce6, which enhances chemiluminescence for imaging of tumor sites and further greatly amplifies the generation of 1 O 2 for photodynamic therapy. The resulting CPPO/Ce6/CuO 2 @PLGA showed an excellent therapeutic effect on tumors and intracellular pathogens in vitro and in vivo . This work may offer a facile strategy to prepare multifunctional CL nanoreactors for imaging-guided elimination of both tumors and tumor-resident intracellular pathogens.