Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) are essential components of the innate immune sensors to cytosolic DNA and elicit type I interferon (IFN). Recent studies have revealed that manganese (Mn) can enhance cGAS and STING activation to viral infection. However, the role of Mn in antitumor immunity has not been explored. Here, we designed a nanoactivator, which can induce the presence of DNA in cytoplasm and simultaneously elevate Mn 2+ accumulation within tumor cells. In detail, amorphous porous manganese phosphate (APMP) NPs that are highly responsive to tumor microenvironment were employed to construct doxorubicin (DOX)-loaded and phospholipid (PL)-coated hybrid nanoparticles (PL/APMP-DOX NPs). PL/APMP-DOX NPs were stably maintained during systemic circulation, but triggered to release DOX for inducing DNA damage and Mn 2+ to augment cGAS/STING activity. We found that PL/APMP-DOX NPs with superior tumor-targeting capacity boosted dendritic cell maturation and increased cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment into the tumor site. Furthermore, the NPs increased production of type I IFN and secretion of pro-inflammatory cytokines (for example, TNF-α and IL-6). Consequently, PL/APMP-DOX NPs exhibited excellent antitumor efficacy and prolonged the lifespan of the tumor-bearing mice. Collectively, we developed a PL-decorated Mn-based hybrid nanoactivator to intensify immune activation and that might provide therapeutic potential for caner immunotherapy.

Cancer-associated fibroblasts (CAFs) are important barriers for nanoparticles (NPs) to deeply penetrate into tumors and severely limit the antitumor efficacy of nanomedicines.

Nitric oxide (NO) is an important biological messenger implicated in tumor therapy. However, current NO release systems suffer from some disadvantages, such as hydrolysis during blood circulation, poor specificity, and robust irradiation for stimuli. Accordingly, we constructed an intracellular enzyme-triggered NO-generator to achieve tumor cytoplasm-specific disruption and localized rapid drug release. Diethylamine NONOate (DEA/NO) was used as a NO donor and conjugated with hyaluronic acid (HA) to form self-assembly micelle (HA-DNB-DEA/NO), and encapsulate chemotherapeutic agent (doxorubicin (DOX)) into its hydrophobic core (DOX@HA-DNB-DEA/NO). After HA receptor mediated internalization into tumor cells, HA shell would undergo digestion into small conjugated pieces by hyaluronidase. Meanwhile, DOX@HA-DNB-DEA/NO also responded to the intratumoral overexpressed glutathion and glutathione S-transferase π, leading to the intracellular NO production and controlled DOX rapid release. In vitro and in vivo results proved the enzyme-dependent and enhanced targeting delivery profile, and demonstrated that NO and DOX could colocate in specific tumor site, which provided a precondition for exerting their synergistic efficacy. Moreover, expression of p53 protein was upregulated in tumor tissue after treatment, indicating that NO induced cell apoptosis mediated by tumor suppressor gene p53. Overall, this intelligent drug loaded NO-generator might perform as an enhancer to realize better clinical outcomes.

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