Injectable Scaffolds for In Vivo Programmed Macrophages Manufacture and Postoperative Cancer Immunotherapy

Cancer recurrence and metastasis after surgical resection is a vital reason of treatment failure. The modification of immune cells through implanted biomaterials is a promising postoperative immunotherapy. Herein, an injectable hydrogel scaffold loaded with engineered exosome mimetics that in vivo recruits and programs endogenous macrophages into M1 binding with anti-CD47 antibody (M1-aCD47 macrophages) for postoperative cancer immunotherapy is developed. Briefly, M1 macrophages-derived exosome mimetics co-modified with vesicular stomatitis virus glycoprotein (VSV-G) and aCD47 (V-M1EM-aCD47) are encapsulated in injectable chitosan hydrogel. Such hydrogel recruits inherent macrophages in situ and releases V-M1EM-aCD47 that programs M2 to M1-aCD47 macrophages. M1-aCD47 macrophages own dual-functions of tumor-homing and enhanced phagocytosis. They can actively target to tumor cells for delivery of aCD47 that blocks the “don't eat me” signal, thereby promoting phagocytosis of macrophages to cancer cells. Furthermore, V-M1EM-aCD47 hydrogel implanted into resection site of 4T1 breast tumor inhibits tumor recurrence and metastasis by phagocytosis of M1-aCD47 macrophages and T cell-mediated immune responses. The findings demonstrate that biomaterials can be designed in vivo to program inherent macrophages, thereby activating the innate and adaptive immune systems for prevention of postoperative tumor recurrence and metastasis.     

Photothermal Lysis of Engineered Bacteria to Modulate Amino Acid Metabolism against Tumors

Bacterial-mediated synergistic cancer therapy (BMSCT) is used as a promising tumor therapy approach. However, there are some disadvantages of bacterial therapy alone to be resolved, such as low tumor suppression rate in the treatment. In this study, a novel light-controlled engineered bacterial material which synergistically regulates amino acid metabolism to fight tumors is developed. It transcribes l -methionine-γ-lyase (MdeA) into Escherichia coli (E. coli) and loads the approved photothermal agent indocyanine green (ICG), namely E. coli-MdeA@ICG. Using the hypoxic tropism of E. coli, genetically engineered bacteria are first loaded with photothermal agents, then selectively accumulate and replicate in the tumor region. Under laser irradiation, photothermal lysis of E. coli-MdeA is performed to release the MdeA and consume the essential amino acid methionine (Met) in the tumor environment. In vitro cell experiments confirm that the E. coli-MdeA + NIR group can reach 90% of the 4T1 cells killing. In 4T1 tumor-bearing mouse models, E. coli-MdeA@ICG shows enhanced antitumor efficacy, along with 91.8% of the tumor growth inhibited. Apoptosis of tumor cells is induced under the dual action of photothermal therapy (PTT) and amino acid metabolism therapy. This strategy provides new ideas for the combination of synthetic biology and nanotechnology in anti-tumor.     

Functionalized DNA Nanomaterials Targeting Toll-Like Receptor 4 Prevent Bisphosphonate-Related Osteonecrosis of the Jaw via Regulating Mitochondrial Homeostasis in Macrophages

Imbalance of macrophage polarization characterized by an increase in the percentage of pro-inflammatory M1 macrophages and a decrease in anti-inflammatory M2 macrophages is considered a critical pathogenic mechanism of bisphosphonate-related osteonecrosis of the jaws (BRONJ). Because high levels of Toll-like receptor 4 (TLR4) mediates mitochondrial dyshomeostasis in Zoledronic Acid (ZA)-treated M1 macrophages, tetrahedral DNA nanomaterial (TDN)-modified with TLR4-siRNA on each vertex (TDN-TLR4-4siR) with excellent biocompatibility is synthesized. This novel TDN-TLR4-4siR nanomaterial reverses the polarization phenotype imbalance decreasing the percentage of M1 RAW264.7 macrophages. Mitochondrial dynamics analysis shows a shift from short rod-like ultrastructure to elongated shapes with more mitochondrial network continuity in ZA-primed M1 macrophages after treatment with TDN-TLR4-4siR, along with elevated expression of Mfn1 and Mfn2. TDN-TLR4-4siR further reduces intracellular ROS production and restored mitochondrial membrane potential. Furthermore, decreased sequestra formation and accelerated healing of the extraction wound are observed in the TDN-TLR4-4siR group, resulting in decreased incidence of rat BRONJ via reprogramming polarized macrophages. Consequently, this study establishes a novel strategy using TDN-TLR4-4siR nanomaterial to regulate mitochondrial homeostasis of polarized macrophages to prevent BRONJ.     

Bioresponsive Self-Reinforcing Sericin/Silk Fibroin Hydrogel for Relieving the Immune-Related Adverse Events in Tumor Immunotherapy

Despite the immense potential of immune checkpoint blockade (ICB) therapy in tumor treatment, its widespread clinical application is currently limited by unsatisfactory curative effect and off-target adverse effect. Herein, an injectable sericin (SS)/silk fibroin (SF) recombinant hydrogel, termed SF-SS-SMC hydrogel, is developed to enable local delivery of anti-CD47 antibody (α CD47). The hydrogel displays self-reinforcement in high H₂O₂ concentration of tumor microenvironment (TME), as the SS/Fe²⁺ supramolecular nanocomplex (SS-SMC) inside the hydrogel converts H₂O₂ to reactive oxygen species (ROS), further triggering additional crosslinking among the SF polymers. Therefore, the SF-SS-SMC hydrogel has an in vivo retention time longer than 21 days and acts as a reservoir for the long-term sustained release of α CD47. More importantly, the SF-SS-SMC hydrogel itself efficiently regulates the remodeling of a protumor immunosuppressive TME to an antitumoral TME through switching of tumor-associated macrophages from an anti-inflammatory M2 phenotype to a proinflammatory M1 phenotype without additional drugs. Based on the combined effect of sustained α CD47 release and TME reprogramming, the SF-SS-SMC hydrogel has satisfactory immunotherapeutic effects in the treatment of local, abscopal, remitting, and metastatic tumors. Further advantages, including low cost of production, simple fabrication, and ease of use, make it promising for commercial mass production.     

Bacteria‐Assisted Selective Photothermal Therapy for Precise Tumor Inhibition

Photothermal therapy (PTT) has drawn extensive research attention as a promising approach for tumor treatment. In this study, a bacteria‐assisted strategy relying on the selective reduction of perylene diimide derivative based supramolecular complex (CPPDI) to radical anions (RAs) by Escherichia coli in hypoxic tumors is developed to realize highly precise PTT of tumors. Noninvasive E. coli are first injected intravenously for selectively accumulating and replicating in the tumor due to the hypoxia tropism. Then, CPPDI is loaded in a peptide‐hybrid matrix metalloproteinase‐2 (MMP‐2) responsive liposome (MRL) and injected intravenously. After accumulated and released from MRL in the tumor where MMP‐2 is overexpressed, CPPDI is reduced by E. coli in the hypoxic tumor environment to produce CPPDI RAs (CRAs), which serve as effective photothermal agents for tumor cells thermal ablation under near‐infrared light irradiation. Since E. coli accumulate and grow in tumor sites selectively, this strategy accurately limits the production of CRAs in tumors for highly selective PTT, which will find great potential for precise tumor inhibition.     

Dual‐Targeting to Cancer Cells and M2 Macrophages via Biomimetic Delivery of Mannosylated Albumin Nanoparticles for Drug‐Resistant Cancer Therapy

Multidrug resistance (MDR) is an issue that is not only related to cancer cells but also associated with the tumor microenvironments. MDR involves the complicated cancer cellular events and the crosstalk between cancer cells and their surroundings. Ideally, an effective system against MDR cancer should take dual action on both cancer cells and tumor microenvironments. The authors find that both the drug‐resistant colon cancer cells and the protumor M2 macrophages highly express two nutrient transporters, i.e., secreted protein acidic and rich in cysteine (SPARC) and mannose receptors (MR). By targeting SPARC and MR, a system can act on both cancer cells and M2 macrophages. Herein the authors develop a mannosylated albumin nanoparticles with coencapsulation of different drugs, i.e., disulfiram/copper complex (DSF/Cu) and regorafenib (Rego). The results show that combination therapy of DSF/Cu and Rego efficiently inhibits the growth of drug‐resistant colon tumor, and the combination has not been reported yet for use in anticancer treatment. The system significantly improves the treatment outcomes in the animal model bearing drug‐resistant tumors. The therapeutic mechanisms involve enhanced apoptosis, upregulation of intracellular ROS, anti‐angiogenesis, and tumor‐associated macrophage “re‐education.” This strategy is characterized by dual targeting to and the simultaneous action on cancer cells and M2 macrophages, with biomimetic codelivery of a novel drug combination.     

Metabolic Regulation of Tumor Microenvironment with Biohybrid Bacterial Bioreactor for Enhanced Cancer Chemo-Immunotherapy

Immunogenic cell death (ICD) induced by specific chemotherapeutic agents is often hampered by the immunosuppressive tumor microenvironment (TME). Here, a bacterial bioreactor E@Fe-DOX, is developed, to enhance ICD-mediated antitumor immunity by in situ manipulation of tumor metabolism-immune interactions. The E@Fe-DOX bioreactor is constructed by depositing doxorubicin-loaded iron-polyphenol nanoparticles on Eubacterium hallii, which can specifically target hypoxic tumor regions and release doxorubicin and Fe³⁺ to induce ICD. In addition, Eubacterium hallii can continuously convert intratumoral lactate to butyrate, which inhibits the polarization of pro-tumoral M2-like macrophages and improves the function of tumor-infiltrating cytotoxic T cells. Furthermore, E@Fe-DOX promotes the formation of immune cell-aggregated tertiary lymph structures (TLS) to augment ICD-induced antitumor immunity. In murine tumor models, E@Fe-DOX significantly inhibits tumor growth and enhances immune checkpoint blockade (ICB) therapy. Overall, the developed living biomaterial offers a promising strategy to potentiate cancer chemo-immunotherapy by continuously regulating the intratumoral immuno-metabolic microenvironment.     

Targeted Delivery of Apoptotic Cell-Derived Nanovesicles prevents Cardiac Remodeling and Attenuates Cardiac Function Exacerbation

The modulation of inflammatory responses plays an important role in the pathobiology of cardiac failure. In a natural healing process, the ingestion of apoptotic cells and their apoptotic bodies by macrophages in a focal lesion result in resolution of inflammation and regeneration. However, therapeutic strategies to enhance this natural healing process using apoptotic cell-derived biomaterials have not yet been established. In this study, apoptotic bodies-mimetic nanovesicles derived from apoptotic fibroblasts (ApoNVs) conjugated with dextran and ischemic cardiac homing peptide (CHP) (ApoNV-DCs) for ischemia-reperfusion (IR)-injured heart treatment are developed. Intravenously injected ApoNV-DCs actively targeted the ischemic myocardium via conjugation with CHP, and are selectively phagocytosed by macrophages in an infarcted myocardium via conjugation with dextran. ApoNV-DCs polarized macrophages from the M1 to M2 phenotype, resulting in the attenuation of inflammation. Four weeks after injection, ApoNV-DCs attenuated cardiac remodeling, preserved blood vessels, and prevented cardiac function exacerbation in IR-injured hearts. Taken together, the findings may open a new avenue for immunomodulation using targeted delivery of anti-inflammatory nanovesicles that can be universally applied for various inflammatory diseases.     

Gelatin-Hyaluronan Click-Crosslinked Cryogels Elucidate Human Macrophage Invasion Behavior

Hydrogel models of metastasis traditionally focus on the invasion of cancer cells; however, other cells in the tumor microenvironment that are associated with metastasis also have the ability to migrate. Macrophage phenotype plays a key role in the tumor microenvironment, yet understanding their migration within tunable 3D in vitro models has been limited. To gain a greater understanding of macrophage invasive behavior, stable and transparent oxime-crosslinked cryogels comprised of click-crosslinked gelatin-oxyamine and hyaluronan-aldehyde (GELox-HAa) are synthesized. Fibronectin-derived, oxyamine-modified PHSRN-RGDSP peptides are incorporated to further mimic the tumor extracellular matrix without impacting cryogel mechanics. It is found that primary human macrophages migrate to a greater depth in cryogels with greater porosity and pore size. To better understand the mechanism of migration, cells are treated with either inhibitors of matrix metalloproteinases (MMPs) or rho-associated protein kinase (ROCK) and a predominantly MMP-mediated mechanism of invasion is found. Macrophage polarization studies reveal that anti-inflammatory, interleukin-4/13 (IL4/IL13)-treated macrophages migrate through cryogels to a greater extent than pro-inflammatory, interferon-gamma/lipopolysaccharide (IFNγ/LPS)-treated cells. Interestingly, polarized macrophages move through cryogels using a combination of amoeboid and mesenchymal migration. These findings of macrophage invasion in this cryogel platform set the stage for their further study in a biomimetic tumor microenvironment.     

Surface-Engineered Extracellular Vesicles with CDH17 Nanobodies to Efficiently Deliver Imaging Probes and Chemo-Photothermal Drugs for Gastric Cancer Theragnostic

Extracellular vesicles (EVs) are widely used as natural nanoparticles to deliver various cargos for disease diagnosis and therapy. However, unmodified EVs cannot efficiently transport the cargos to desired sites due to non-specific uptake. Here, a delivery system is designed to display nanobodies against cadherin 17 (CDH17) on the surface of EVs isolated from HEK-293 cells and loaded with dye Indocyanine green (ICG) and/or anti-cancer drug dinitroazetidine derivative RRx-001, a blocker for CD47/ signal regulatory protein alpha (SIRPα) axis. CDH17 is a promising target for gastric cancer (GC) therapy. In this study, ICG loaded in the EVs engineered with CDH17 nanobodies can realize rapid tumor imaging in a CDH17-positive GC model and can produce significant anti-tumor photothermal therapeutic (PTT) effect after irradiation. Meanwhile, PTT effect can induce immunogenic cell death and macrophage polarization from M2 to M1 phenotype. The engineered EVs loaded with RRx-001 can significantly repress GC tumor growth. Finally, dual loading of ICG/RRx-001 in engineered EVs show maximal anti-tumor efficacy in both cancer cell and patient-derived GC models after only single injection. Collectively, CDH17 nanobody-functionalized EVs loaded with ICG and/or RRx-001 hold great promise to image and treat GC by combining fluorescent dye-induced PTT with chemotherapy.     

Self-Targeted Co-Delivery of an Antibiotic and a Cancer-Chemotherapeutic from Synthetic Liposomes for the Treatment of Infected Tumors

Intra-tumor bacteria promote tumor growth and inactivate cancer-chemotherapeutics, causing poor treatment prognoses. Combined administration of cancer-chemotherapeutics and antibiotics may disturb the oral and intestinal microflora in critically-ill patients. To establish intra-tumor co-delivery of cancer-chemotherapeutics and antibiotics, gemcitabine and ciprofloxacin are loaded in so-called “self-targeting”, highly blood-compatible, synthetic DCPA-H₂O liposomes equipped with complexed water for pH-responsiveness. Liposomal pH-responsiveness can be maintained by in-shell loading of gemcitabine and in-core loading of ciprofloxacin. These dual-loaded liposomes are stealthily transported in the blood circulation to accumulate in the acidic environment of an infected tumor. Upon tumor self-targeting, liposomes are fused with tumor cells and infecting bacteria and are disassembled to simultaneously release gemcitabine and ciprofloxacin. Treatment of mice with these self-targeting liposomes yields significantly higher responses of Escherichia coli infected tumors with respect to both infection and tumor volume than gemcitabine and ciprofloxacin co-delivered from non-self-targeting liposomes or free gemcitabine with or without ciprofloxacin in solution.     

Implication of blood flow in hyperthermic treatment of tumors

Tumor blood flow varies significantly depending on the type, age, and size of tumors. Furthermore, the distribution of blood perfusion in tumors is quite heterogeneous. Blood flow in tumors may or may not be greater than that in the surrounding normal tissues at normothermic conditions. When heated at 41-430C, tumor blood flow either remains unchanged or increases slightly, usually by a factor of less than 2. The newly formed tumor vessels appear to be so vulnerable to heat that the blood flow decreases at 42-43' C in most of the animal tumors studied so far. By contrast, the blood flow in normal tissues, e. g., skin and muscle, increases by a factor of 3-20 upon heating at 42-450C. Consequently, the heat dissipation by blood flow becomes greater in normal tissues than in tumors during heating, and thereby a greater temperature rise in tumors may occur, resulting in greater damage in tumor relative to normal tissues. The intrinsically acidic intratumor environment becomes further acidic upon heating and accentuates the thermal damage on the tumor cells. Blood perfusion appears to be implicated in such a heat-induced increase in the intratumor acidity.     

Nanoagonist-Mediated GSDME-Dependent Pyroptosis Remodels the Inflammatory Microenvironment for Tumor Photoimmunotherapy

Immunotherapy, especially immune checkpoint blockade (ICB) antibody immunotherapy, has revolutionized the treatment ways of cancers and provided remarkable clinical benefits for multiple cancers. However, the efficacy of immunotherapy in tumors with an immune-excluded or immune-suppressed phenotype is dismal due to the lack or paucity of immune infiltration in the tumor microenvironment. Herein, an emerging photoimmunotherapy based on remodeling the inflammatory microenvironment is reported, ascribed to nanoagonist-mediated gasdermin E (GSDME)-dependent pyroptosis and providing positive feedback to activate anti-PD-1 immunotherapy. An iridium-based photosensitizer (IrP) carrying methyltransferase inhibitor RG108 (R@IrP) lead to rapid cell pyroptosis via the caspase-3/GSDME pathway under the light activation. Furthermore, light-elicited pyroptosis synergized with anti-PD-1 to induce anti-tumor photoimmunotherapy. The pro-inflammatory factors released by pyroptotic cells remodel the inflammatory microenvironment and recruit immune cells to kill tumor cells, resulting in CD8⁺ cytotoxic T lymphocytes activation, PD-1 expression enhancement, and dendritic cell slightly maturation. Collectively, these findings present a synergistic strategy of photoimmunotherapy, that is, turning immunological cold tumors into hot tumors that can respond to anti-PD-1-based immunotherapy via precise pathway regulation.     

Injectable Adhesive Hydrogel as Photothermal-Derived Antigen Reservoir for Enhanced Anti-Tumor Immunity

Low vaccine immunogenicity and tumor heterogenicity greatly limit the therapeutic effect of tumor vaccine. In this study, a novel injectable adhesive hydrogel, based on thermosensitive nanogels containing catechol groups and loaded with in situ-forming MnO₂ nanoparticles, is constructed to overcome these issues. The concentrated nanogel dispersion transforms into an adhesive hydrogel in situ after intratumoral injection. The photothermal effect of the loaded MnO₂ nanoparticles induces immunogenic cell death to release mass autologous tumor-derived protein antigens under near-infrared irradiation, which act as ideal immune stimulating substances avoiding the problem of tumor heterogenicity and are captured by the in situ-forming adhesive hydrogel. The antigens-captured adhesive hydrogel acts as an “antigen reservoir” and releases these captured antigens to recruit more dendritic cells to stimulate an intensive and lasting anti-tumor immune response mediated by CD8⁺ T cells. The primary tumors can be almost completely disappeared within 4 days without relapse, and the growth of the distal tumors and rechallenged tumors are also effectively inhibited by the treatment with the injectable adhesive hydrogel-based photothermal therapy. Therefore, the proposed “antigen reservoir” strategy shows the great potential application as an in situ-forming personalized vaccine to enhancing the cancer immune therapy.     

Copper Sulfide Nanoparticle-Redirected Macrophages for Adoptive Transfer Therapy of Melanoma

Adoptive cell therapy (ACT) has achieved landmark advances in treating cancer in clinic. Recent advances in ACT of macrophages engineered to express chimeric antigen receptors (CARs) have shown effectiveness in treating solid tumors. However, the CAR-macrophage therapy is dependent on tumor antigen recognition and gene editing methods. Herein, an adoptive macrophage therapy is presented through copper sulfide nanoparticle-regulation that exhibits substantial antitumor effect in melanoma-bearing mice, without the need for tumor antigen repertoire. Bone marrow derived macrophages (BMDMs) incubated with the nanoparticles promote the cellular production of reactive oxygen species (ROS) through dynamin-related protein 1 (Drp1)-mediated mitochodrial fission. The high intracellular ROS level directs BMDMs polarization toward M1 phenotype by classical IKK-dependent NF-κB activation. Moreover, the copper sulfide nanoparticle-stimulated BMDMs (CuS-MΦ) reduce the expression of programmed death-1 (PD-1) and exhibit enhanced phagocytic and digestive ability. Intratumoral transfer of CuS-MΦ significantly prolongs the median survival time of the tumor-bearing mice, remodels the tumor microenvironment, and elicits systemic antitumor immunity. These results suggest a cancer therapeutic approach of adoptively transferred macrophages through the induction of intracellular ROS with nanomaterials.     

A Chemoimmunotherapy Nanogel Enables Efficient Delivery of Interleukin-2 and Induction of Immunogenic Cell Death for Effective Cancer Therapy

Interleukin-2 (IL-2) is one of the first FDA-approved immunotherapeutics, but its use is limited by toxicity and low efficacy. In addition, all immunotherapies are limited by the immunosuppressive and desmoplastic microenvironment of “immunologically cold” tumors, such as pancreatic ductal adenocarcinoma (PDAC) or hepatocellular carcinoma (HCC) with advanced liver fibrosis. Here, a new chemoimmunotherapy nanogel (IL2-Pt@Nanogel) for dual delivery of IL-2 and the type II immunogenic cell death inducer Pt-NHC that reduces the immunosuppressive phenotype of tumor-associated macrophages and diminishes regulatory T cell infiltration by inducing the production of type I interferon (IFN) by cancer cells is reported. Combining the angiotensin II receptor blocker losartan with IL2-Pt@Nanogel treatment reduces desmoplasia and reprogrammes the microenvironment of PDAC and HCC toward an immunostimulatory one. These effects result in potent anti-tumor efficacy in models of primary and metastatic PDAC and HCC with underlying liver fibrosis. This study presents a strategy for IL-2-based chemoimmunotherapy with the potential for clinical translation to treat solid tumors.     

A Nano “Immune-Guide” Recruiting Lymphocytes and Modulating the Ratio of Macrophages from Different Origins to Enhance Cancer Immunotherapy

Artificially modulating the type, density, and location of immune cells within the tumor microenvironment can suppress tumor growth and efficiently promote current immunotherapy. In this study, a magnetite nanoparticle-based “immune-guide” is developed by the functionalization of magnetite nanoparticles with hyaluronic acid (HA). HA, an extracellular matrix component, can target various CD44-overexpressing tumors and mediate the adhesion and migration of multiple types of immune cells. Thus, HA-functionalized magnetite nanoparticles (HA-PDA@Fe₃O₄) can highly efficiently accumulate in breast cancer and penetrate deep into the tumor parenchyma. Consequently, high intratumoral concentration of HA, serving as a “guidepost,” can directly recruit lymphocytes and elicit more chemokine production through cascading amplification effects, turning the immune “cold” tumor into a “hot” one. More importantly, HA-PDA@Fe₃O₄ can effectively remodel the diversity, origin, and activation of tumor-associated macrophages by recruiting and activating infiltrating macrophages, while simultaneously reducing the M2-maintained tissue-resident macrophages. Thus, HA-PDA@Fe₃O₄ synergistically improves T cell- and macrophage-based immunotherapies as well as interferes with the formation of premetastatic niches in the lung. By redistributing the localization of HA in tumors by using magnetite nanoparticles, this study provides a unique strategy to modulate the tumor immune microenvironment and potentiate tumor immunotherapies by using biocompatible nanomaterials without any therapeutic drug.     

Living Cell-Derived Intelligent Nanobots for Precision Oncotherapy

The progress of precision oncology medicine is always limited by the tumor off-targeting, the drug side effects, and the treatment inefficiency due to the complex and ever-changing tumor microenvironment. Living cells, such as blood cells and immune cells, exhibit natural tumor tropism, controllable physicochemical modification, and excellent biocompatibility, which provide an advantageous pathway for innovative and efficient tumor suppression. Armed with nanoengineering techniques, artificial living cells harness their inherent biological properties to precisely identify and eradicate tumors, demonstrating broad biological application prospects and great transformational potential in personalized cancer therapy. Here, the recent advances of living cell-based bionanobots including platelets, red blood cells, neutrophil, macrophage, and CAR-T cells for cancer precision therapy and immune regulation are summarized, and the efficient anti-tumor strategies for engineering living cell nanorobots to overcome complex biological barriers and immune suppression are also outlined (e.g., immunotherapy, sonodynamic therapy, chemo/radiotherapy, and phototherapy). In addition, the study discusses the advantages, limitations, and current challenges of artificial living cell-based drug delivery systems, and provide perspectives on the future development of living cell-mediated precision tumor nanomedicine.     

Designing Bioinspired 2D MoSe2 Nanosheet for Efficient Photothermal‐Triggered Cancer Immunotherapy with Reprogramming Tumor‐Associated Macrophages

Nonspecific absorption and clearance of nanomaterials during circulation is the major cause for treatment failure in nanomedicine‐based cancer therapy. Therefore, herein bioinspired red blood cell (RBC) membrane is employed to camouflage 2D MoSe₂ nanosheets with high photothermal conversion efficiency to achieve enhanced hemocompatibility and circulation time by preventing macrophage phagocytosis. RBC–MoSe₂‐potentiated photothermal therapy (PTT) demonstrates potent in vivo antitumor efficacy, which triggers the release of tumor‐associated antigens to activate cytotoxic T lymphocytes and inactivate the PD‐1/PD‐L1 pathway to avoid immunologic escape. Furthermore, in the ablated tumor microenvironment, the tumor‐associated macrophages are effectively reprogrammed to tumoricidal M1 phenotype to potentiate the antitumor action. Taken together, this biomimetic functionalization thus provides a substantial advance in personalized PTT‐triggered immunotherapy for clinical translation.     

Cationic Polymer Modified Mesoporous Silica Nanoparticles for Targeted siRNA Delivery to HER2+ Breast Cancer

In vivo delivery of siRNAs designed to inhibit genes important in cancer and other diseases continues to be an important biomedical goal. A new nanoparticle construct that is engineered for efficient delivery of siRNA to tumors is now described. The construct comprises a 47‐nm mesoporous silica nanoparticle core coated with a crosslinked polyethyleneimine–polyethyleneglycol copolymer, carrying siRNA against the human epidermal growth factor receptor type 2 (HER2) oncogene, and coupled to the anti‐HER2 monoclonal antibody (trastuzumab). The construct is engineered to increase siRNA blood half‐life, enhance tumor‐specific cellular uptake, and maximize siRNA knockdown efficacy. The optimized anti‐HER2 nanoparticles produce apoptotic death in HER2 positive (HER2⁺) breast cancer cells grown in vitro, but not in HER2 negative (HER2^?) cells. One dose of the siHER2–nanoparticles reduces HER2 protein levels by 60% in trastuzumab‐resistant HCC1954 xenografts. Administration of multiple intravenous doses over 3 weeks significantly inhibits tumor growth (p < 0.004). The siHER2‐nanoparticles have an excellent safety profile in terms of blood compatibility and low cytokine induction, when exposed to human peripheral blood mononuclear cells. The construct can be produced with high batch‐to‐batch reproducibility and the production methods are suitable for large‐scale production. These results suggest that this siHER2‐nanoparticle is ready for clinical evaluation.