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Recently, fluorescent dyes with a structure-inherent mitochondria-targeting capability have obtained great attention as single-molecule self-reporting theranostic agents to distinguish cancer cells from normal cells. However, there was little attempt using these dyes as a self-reporting ligand for cancer-targeted delivery of nanomaterials or drugs for personalized therapy. Herein, we developed a mitochondria-localized multifunctional nanodelivery system for cancer-targeted drug delivery and dual-modal imaging. First, a series of cyanine-structural small molecules with different-charged substituent groups have been screened based on their mitochondria targeting capability. Furthermore, the cyanine-structural molecule with the best mitochondria-targeting ability was decorated on iron oxide nanoparticles (IONP) for dual-modal imaging. The nanoprobes entered into the cancer cell via the organic anion transporting polypeptide (OATP) pathway and anchored on mitochondria due to the strong interaction between the negative mitochondria membrane and the lipophilic cationic cyanine dye. This work opened an avenue using small molecules with structure-inherent-targeting and self-reporting characteristics as a chemical ligand to develop cancer-targeting and subcellular-localized delivery system.

One approach to cancer immunotherapy is the repolarization of immunosuppressive tumor-associated macrophages (TAMs) to antitumor M1 macrophages. The present study developed galactose-functionalized zinc protoporphyrin IX (ZnPP) grafted poly(l-lysine)- b-poly(ethylene glycol) polypeptide micelles (ZnPP PM) for TAM-targeted immunopotentiator delivery, which aimed at in vivo repolarization of TAMs to antitumor M1 macrophages. The outcomes revealed that ROS-inducing ZnPP PM demonstrated specificity for the in vitro and in vivo targeting of macrophages, elevated the level of ROS, and lowered STAT3 expression in BM-TAMs. Poly I:C (PIC, a TLR3 agonist)-loaded ZnPP PM (ZnPP PM/PIC) efficiently repolarized TAMs to M1 macrophages, which were reliant on ROS generation. Further, ZnPP PM/PIC substantially elevated the activated NK cells and T lymphocytes in B16-F10 melanoma tumors, which caused vigorous tumor regression. Therefore, the TAM-targeted transport of an immunologic adjuvant with ZnPP-grafted nanovectors may be a potential strategy to repolarize TAMs to M1 macrophages in situ for effective cancer immunotherapy.