A hybrid bacterium with tumor-associated macrophage polarization for enhanced photothermal-immunotherapy.

Remodeling the tumor microenvironment through reprogramming tumor-associated macrophages (TAMs) and increasing the immunogenicity of tumors via immunogenic cell death (ICD) have been emerging as promising anticancer immunotherapy strategies. However, the heterogeneous distribution of TAMs in tumor tissues and the heterogeneity of the tumor cells make the immune activation challenging. To overcome these dilemmas, a hybrid bacterium with tumor targeting and penetration, TAM polarization, and photothermal conversion capabilities is developed for improving antitumor immunotherapy in vivo. The hybrid bacteria (B.b@QDs) are prepared by loading Ag2S quantum dots (QDs) on the Bifidobacterium bifidum (B.b) through electrostatic interactions. The hybrid bacteria with hypoxia targeting ability can effectively accumulate and penetrate the tumor tissues, enabling the B.b to fully contact with the TAMs and mediate their polarization toward M1 phenotype to reverse the immunosuppressive tumor microenvironment. It also enables to overcome the intratumoral heterogeneity and obtain abundant tumor-associated antigens by coupling tumor penetration of the B.b with photothermal effect of the QDs, resulting in an enhanced immune effect. This strategy that combines B.b-triggered TAM polarization and QD-induced ICD achieved a remarkable inhibition of tumor growth in orthotopic breast cancer.

A near-infrared light-responsive extracellular vesicle as a "Trojan horse" for tumor deep penetration and imaging-guided therapy.

How to make the nanoparticles evade immune surveillance and deeply penetrate the tumor tissues is of great importance to maximize the therapeutic efficacy of nanomedicines. Here, a near-infrared (NIR) light-responsive extracellular vesicle as a nanoplatform is developed to realize long circulation in blood, deep penetration in tumor tissues and rapid body elimination after the treatment. Like a "Trojan horse", the nanoplatform is obtained by hiding the anti-tumor soldiers (DOX and 4.2 nm Ag2S quantum dots (QDs)) into the macrophage cell-secreted vesicle through electroporation. The natural composition and tumor targeting activity of the extracellular vesicles enable the nanoplatform to achieve a high accumulation in tumor and the in vivo biodistribution can be monitored by NIR fluorescence imaging of the Ag2S QDs. After the nanomedicines accumulate at the tumor sites, the soldiers will be released from the "Trojan horse" by utilizing the NIR photothermal effect of the Ag2S QDs. The released ultrasmall QDs and DOX can penetrate the whole tumor with a diameter of about 9 mm and effectively kill the tumor cells. Moreover, the inorganic QDs can be rapidly excreted from the body through renal clearance after the treatment to avoid the potential toxicity.

A NIR light triggered disintegratable nanoplatform for enhanced penetration and chemotherapy in deep tumor tissues.

Poor penetration and resultant low accumulation of nanomedicines in deep tumor tissues greatly reduce the chemotherapeutic efficiency. How to maximize the tumor accumulation is still a great challenge in the development of nanocarriers. Here, we developed a cyclic Arg-Gly-Asp-Phe-Lys peptide (cRGD) modified and near-infrared (NIR) light triggered disintegratable liposomal nanoplatform (PAM/Pt@IcLipo), where photosensitizer indocyanine green (ICG) was loaded in the out layer and polyamindoamine (PAMAM) dendrimers grafting cisplatin prodrug (PAM/Pt) were encapsulated inside. The cRGD ligands render the liposomes to target αvß3 integrin receptors overexpressed by vascular endothelial cells in tumor tissues. Long blood circulation can be achieved owing to the relative large size (~162 nm) of the liposomes. When irradiated by NIR light locally at tumor site, ICG heating detonated the thermosensitive liposomes to release the small sized PAM/Pt nanoparticles (~8.6 nm), which were capable of penetrating into the deep tumor tissue. The in vivo results also showed that the PAM/Pt@IcLipo could significantly improve the penetration of cisplatin drug in deep tumor tissues under NIR light irradiation, resulting in an excellent antitumor activity. This nanoplatform solved the dilemma of long blood circulation of large sized nanoparticles and deep penetration of small sized nanoparticles, opening up a new strategy in the development of nanomedicines for cancer therapy.