Dual Closed-Loop of Catalyzed Lactate Depletion and Immune Response to Potentiate Photothermal Immunotherapy.

Lactate accumulation in the solid tumor is highly relevant to the immunosuppressive tumor microenvironment (TME). Targeting lactate metabolism significantly enhances the efficacy of immunotherapy. However, lactate depletion by lactate oxidase (LOX) consumes oxygen and results in the aggravated hypoxia situation, counteracting the benefit of lactate depletion. Beyond the TME regulation, it is necessary to initiate the effective immunity cycle for therapeutic purposes. In this fashion, dual close-loop of catalyzed lactate depletion and immune response by a rational material design are established to address this issue. Here, we constructed PEG-modified mesoporous polydopamine nanoparticles with Cu2+ chelation and LOX encapsulation (denoted as mCuLP). After mCuLP nanosystems targeting into the tumor sites, released LOX consumes lactate to H2O2. Subsequently, the produced H2O2 is further catalyzed by Cu2+-chelated mPDA to produce oxygen, supplying the oxygen source for the closed-loop of lactate depletion. Meanwhile, the mild PTT caused by the photothermal mPDA induces ICD of tumor cells to promote DC maturation and then T lymphocyte infiltration to kill tumor cells, which forms another closed-loop for cancer immunity. Therefore, this dual closed-loop strategy of mCuLP nanosystems effectively inhibits tumor growth, providing a promising treatment modality to cancer immunotherapy.

Remotely boosting hyaluronidase activity to normalize the hypoxic immunosuppressive tumor microenvironment for photothermal immunotherapy.

Tumor hyaluronan (HA) accumulation is closely associated with the formation of a hypoxic microenvironment that is highly immunosuppressive and severely hinders the efficacy of antitumor therapeutics. To address this problem, we develop an effective HA attenuation strategy that uses an integrated nanosystem based on mesoporous polydopamine (mPDA) with excellent photothermal conversion efficiency to boost hyaluronidase (HAase) activity remotely. Upon light irradiation, the thermal effect generated by mPDA not only directly kills tumor cells that produces an in situ vaccine effect, but also significantly boosts HAase activity (∼5 folds), leading to marked HA break down. Photoheat and HA degradation synergistically reduce tumor HIF-1α expression and reverse immunosuppressive responses. Using the synergistic treatment in a breast cancer model, we find decreased infiltration of immunosuppressive cells, including myeloid-derived suppressor cells, M2 macrophages, and regulatory T cells, increased immune-activated cells, such as mature dendritic cells and CD8+ T cells, and reduced immune checkpoint PD-L1 expression. The resulting relief from tumor microenvironment immunosuppression significantly contributes to an enhanced antitumor effect. This study provides an effective strategy to improve the hypoxic tumor microenvironment and simultaneously promote immune-mediated tumor regression.

Targeting the Negative Feedback of Adenosine-A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy.

The metabolite adenosine plays an important immunosuppressive role in the tumor microenvironment (TME) through its ligation with the metabolic checkpoint adenosine 2A receptor (A2AR). Here, an adenosine-A2AR negative feedback pathway is highlighted during photothermal-induced immunogenic cell death (ICD). Adenosine, hydrolyzed from ATP, is amplified during the photothermal-induced ICD process. It is possible to achieve a robust ICD-based immunotherapy via targeting the adenosine-A2AR metabolic pathway. In this regard, an A2AR inhibitor-loaded polydopamine nanocarrier masked by an acid-sensitive PEG shell is designed to enable tumor-specific delivery and photothermal-induced ICD simultaneously. Upon reaching the acidic TME, the PEG shell selectively detaches and exposes the adhesive polydopamine layer, causing the inhibitors to accumulate at the tumor tissue. The accumulated inhibitors attenuate adenosine's metabolically suppressive effect and strengthen the ICD immune response. It occurs through promoting dendritic cell (DC) activation, increasing CD8+ T lymphocyte infiltration, and reducing the myeloid-derived suppressor cell (MDSC) population. Furthermore, this synergistic therapy significantly regresses the primary tumor, inhibits distal tumor growth, and prevents lung metastasis. The study highlights a strategy to enhance the immunotherapy efficacy of ICD by blocking the metabolic checkpoint A2AR using advanced nanomaterials.

Nanofactory for metabolic and chemodynamic therapy: pro-tumor lactate trapping and anti-tumor ROS transition.

Lactate plays a critical role in tumorigenesis, invasion and metastasis. Exhausting lactate in tumors holds great promise for the reversal of the immunosuppressive tumor microenvironment (TME). Herein, we report on a "lactate treatment plant" (i.e., nanofactory) that can dynamically trap pro-tumor lactate and in situ transformation into anti-tumor cytotoxic reactive oxygen species (ROS) for a synergistic chemodynamic and metabolic therapy. To this end, lactate oxidase (LOX) was nano-packaged by cationic polyethyleneimine (PEI), assisted by a necessary amount of copper ions (PLNPCu). As a reservoir of LOX, the tailored system can actively trap lactate through the cationic PEI component to promote lactate degradation by two-fold efficiency. More importantly, the byproducts of lactate degradation, hydrogen peroxide (H2O2), can be transformed into anti-tumor ROS catalyzing by copper ions, mediating an immunogenic cell death (ICD). With the remission of immunosuppressive TME, ICD process effectively initiated the positive immune response in 4T1 tumor model (88% tumor inhibition). This work provides a novel strategy that rationally integrates metabolic therapy and chemodynamic therapy (CDT) for combating tumors.

Photosensitizer-Laden Neutrophils Are Controlled Remotely for Cancer Immunotherapy.

By incorporating an artificial reactive oxygen species (ROS) generation mechanism, a biotic/abiotic integration is designed to improve the anti-tumor effect of neutrophils by artificially potentiating their ROS effector mechanism in a remotely controlled route. Specifically, the photosensitizer Ce6 is nano-packaged by the albumin BSA to achieve biocompatible and efficient integration with neutrophils (NEs). Reinfusion of the engineered NEs into 4T1 tumor-bearing mice led to more Ce6 accumulation in tumors relative to Ce6 nanoformulation. At the peak of accumulation, tumor illumination activates the embedded Ce6 for ROS generation and NETosis formation. Because of the ROS-intensified cytolytic effect, the growth of 4T1 tumors is inhibited significantly. The photo-controlled process largely avoids the off-target effects observed frequently in current cell therapies. The strategy directly generates ROS effector molecules with spatiotemporal precision. This engineering approach is able to potentiate the native capacity of immune cells independent of the tumor microenvironment.

Cell membrane biomimetic nanoparticles for inflammation and cancer targeting in drug delivery.

Nanoparticle capture and elimination by the immune system are great obstacles for drug delivery. Camouflaging nanoparticles with cell membrane represents a promising strategy to communicate and negotiate with the immune system. As a novel class of nanotherapeutics, such biomimetic nanoparticles inherit specific biological functionalities of the source cells (e.g., erythrocytes, immune cells, cancer cells and platelets) in order to evade immune elimination, prolong circulation time, and even target a disease region by virtue of the homing tendency of the cell membrane protein. In this review, we begin with an overview of different cell membranes that can be utilized to create a biointerface on nanoparticles. Subsequently, we elaborate on the state-of-the-art of cell membrane biomimetic nanoparticles for drug delivery. In particular, a summary of data on circulation capacity and targeting efficiency by camouflaged nanoparticles is presented. In addition to cancer therapy, inflammation treatment, as an emerging application of biomimetic nanoparticles, is specifically included. The challenges and outlook of this technology are discussed.