Detachable Dual-Targeting Nanoparticles for Improving the Antitumor Effect by Extracellular Matrix Depletion.

In the tumor microenvironment (TME), the extracellular matrix (ECM) produced by cancer-associated fibroblasts (CAFs) forms a dense barrier that prevents nanodrugs from penetrating into deep tumor sites, leading to unsatisfactory therapeutic effects. Recently, it has been found that ECM depletion and using small-sized nanoparticles are effective strategies. Herein, we reported a detachable dual-targeting nanoparticle (HA-DOX@GNPs-Met@HFn) based on reducing ECM for enhancing penetration. When these nanoparticles reached the tumor site, the nanoparticles were divided into two parts in response to matrix metalloproteinase-2 overexpressed in TME, causing a decrease in the nanoparticle size from about 124 to 36 nm. One part was Met@HFn, which was detached from the surface of gelatin nanoparticles (GNPs), which effectively targeted tumor cells and released metformin (Met) under acidic conditions. Then, Met downregulated the expression of the transforming growth factor ß by the adenosine monophosphate-activated protein kinase pathway to inhibit the activity of CAFs, thereby suppressing the production of ECM including α-smooth muscle actin and collagen I. The other was the small-sized hyaluronic acid-modified doxorubicin prodrug with autonomous targeting ability, which was gradually released from GNPs and internalized into deeper tumor cells. Intracellular hyaluronidases triggered the release of doxorubicin (DOX), which killed tumor cells by inhibiting DNA synthesis. The combination of size transformation and ECM depletion enhanced the penetration and accumulation of DOX in solid tumors. Therefore, the tumor chemotherapy effect was greatly improved.

Co-delivery of celastrol and lutein with pH sensitive nano micelles for treating acute kidney injury.

To treat acute kidney injury with high efficiency and low toxicity, a novel nanoplatform was developed to remove excess reactive oxygen species (ROS). Lutein (LU) and celastrol (Cel) were loaded into low molecular weight chitosan (CS) to prepare Cel@LU-CA-CS nanomicelles. Renal tubular epithelial (HK-2) cell uptake experiments showed that the drugs could be internalized in renal tubular via the megalin receptor. In this study, the amide bond formed by the reaction of citraconic anhydride (CA) with an amino group of CS could be destroyed under acidic conditions. Therefore, the drugs were released in HK-2 cells due to the acidic environment of the lysosome. In vitro studies showed that the nanomicelles could reduce toxicity in non-target organs and enhance therapeutic efficacy in acute kidney injury (AKI). In addition, Cel@LU-CA-CS micelles had alleviated kidney oxidative stress disorder and stabilized the mitochondrial membrane potential quickly. Next, in vivo studies proved that Cel@LU-CA-CS micelles could inhibit the activation of the NF-κB p65 and p38 MAPK inflammatory signaling pathways. Therefore, the micelles further reduced the overexpression of related inflammatory factors. In conclusion, Cel@LU-CA-CS nanomicelles could treat AKI with high efficiency and low toxicity, and inhibit renal fibrosis.

Cascade nanozymes based on the "butterfly effect" for enhanced starvation therapy through the regulation of autophagy.

Although tumor starvation therapy has been proven to be an excellent method for tumor therapy, its efficiency may be weakened by autophagy, a self-protection mechanism exerted by tumors under starvation stress. Interestingly, over-activated autophagy not only improves the efficacy of starvation therapy, but also induces autophagic death. Herein, we report cascade nanozymes for enhanced starvation therapy by inducing over-activated autophagy. First, glucose oxidase (GOx) modified metal-organic frameworks (NH2-MIL88, MOF) were constructed (MOF-GOx). After loading with curcumin (Cur), Cur@MOF-GOx was further decorated with tumor-targeting hyaluronic acid (HA) to obtain Cur@MOF-GOx/HA nanozymes. GOx can catalyze glucose into H2O2 and gluconic acid, which not only leads to tumor starvation, but also provides reactants for the Fenton reaction mediated by the MOF to generate hydroxyl radicals (˙OH) for chemo-dynamic therapy. Most importantly, protective autophagy caused by tumor starvation can be over-activated by Cur to convert autophagy from pro-survival to pro-death, realizing augmented anticancer therapy efficacy. With these cascade reactions, the synergistic action of starvation, autophagy and chemo-dynamic therapy was realized. Generally, the introduction of Cur@MOF-GOx/HA into tumor cells leads to a "butterfly effect", which induces enhanced starvation therapy through subsequent autophagic cell death to completely break the self-protective mechanism of cancer cells, and generate ˙OH for chemo-dynamic therapy. Precise design allows for the use of cascade nanozymes to realize efficient cancer treatment and restrain metastasis.

Mild Acid-Responsive "Nanoenzyme Capsule" Remodeling of the Tumor Microenvironment to Increase Tumor Penetration.

Dense extracellular matrix (ECM) severely impedes the spread of drugs in solid tumors and induces hypoxia, reducing chemotherapy efficiency. Different proteolytic enzymes, such as collagenase (Col) or bromelain, can directly attach to the surface of nanoparticles and improve their diffusion, but the method of ligation may also impair the enzymatic activity due to conformational changes or blockage of the active site. Herein, a "nanoenzyme capsule" was constructed by combining collagenase nanocapsules (Col-nc) with heavy-chain ferritin (HFn) nanocages encapsulating the chemotherapy drug doxorubicin (DOX) to enhance tumor penetration of the nanoparticles by hydrolyzing collagen from the ECM. Col-nc could protect the activity of the enzyme before reaching the site of action while being degraded under mildly acidic conditions in tumors, and the released proteolytic enzyme could digest collagen. In addition, HFn as a carrier could effectively load DOX and had a self-targeting ability, enabling the nanoparticles to internalize into cancer cells more effectively. From in vivo and in vitro studies, we found that collagen was effectively degraded by Col-nc/HFn(DOX) to increase the accumulation and penetration of nanoparticles in the solid tumor site and could alleviate hypoxia inside the tumor to enhance the antitumor effects of DOX. Therefore, the strategy of increasing nanoparticle penetration in this system is expected to provide a potential approach for the clinical treatment of solid tumors.