Virus-Inspired Glucose and Polydopamine (GPDA)-Coating as an Effective Strategy for the Construction of Brain Delivery Platforms.

The ability of drugs to cross the blood-brain barrier (BBB) is crucial for treating central nervous system (CNS) disorders. Inspired by natural viruses, here we report a glucose and polydopamine (GPDA) coating method for the construction of delivery platforms for efficient BBB crossing. Such platforms are composed of nanoparticles (NPs) as the inner core and surface functionalized with glucose-poly(ethylene glycol) (Glu-PEG) and polydopamine (PDA) coating. Glu-PEG provides selective targeting of the NPs to brain capillary endothelial cells (BCECs), while PDA enhances the transcytosis of the NPs. This strategy is applicable to gold NPs (AuNPs), silica, and polymeric NPs, which achieves as high as 1.87% of the injected dose/g of brain in healthy brain tissues. In addition, the GPDA coating manages to deliver NPs into the tumor tissue in the orthotopic glioblastoma model. Our study may provide a universal strategy for the construction of delivery platforms for efficient BBB crossing and brain drug delivery.

Orchestrated Cytosolic Delivery of Antigen and Adjuvant by Manganese Ion-Coordinated Nanovaccine for Enhanced Cancer Immunotherapy.

Cancer vaccines have received tremendous attention in cancer immunotherapy due to their capability to induce a tumor-specific immune response. However, their effectiveness is compromised by the insufficient spatiotemporal delivery of antigens and adjuvants in the subcellular level to induce a robust CD8+ T cell response. Herein, a cancer nanovaccine G5-pBA/OVA@Mn is prepared through multiple interactions of manganese ions (Mn2+), benzoic acid (BA)-modified fifth generation polyamidoamine (G5-PAMAM) dendrimer, and the model protein antigen ovalbumin (OVA). In the nanovaccine, Mn2+ not only exerts a structural function to assist OVA loading as well as its endosomal escape, but works as an adjuvant of stimulator of interferon genes (STING) pathway. These collaboratively facilitate the orchestrated codelivery of OVA antigen and Mn2+ into cell cytoplasm. Vaccination with G5-pBA/OVA@Mn not only shows a prophylactic effect, but also significantly inhibits growth against B16-OVA tumors, indicating its great potential for cancer immunotherapy.

Joint Estimation for Time Delay and Direction of Arrival in Reconfigurable Intelligent Surface with OFDM.

Recently, the joint estimation for time delay (TD) and direction of arrival (DOA) has suffered from the high complexity of processing multi-dimensional signal models and the ineffectiveness of correlated/coherent signals. In order to improve this situation, a joint estimation method using orthogonal frequency division multiplexing (OFDM) and a uniform planar array composed of reconfigurable intelligent surface (RIS) is proposed. First, the time-domain coding function of the RIS is combined with the multi-carrier characteristic of the OFDM signal to construct the coded channel frequency response in tensor form. Then, the coded channel frequency response covariance matrix is decomposed by CANDECOMP/PARAFAC (CPD) to separate the signal subspaces of TD and DOA. Finally, we perform a one-dimensional (1D) spectral search for TD values and a two-dimensional (2D) spectral search for DOA values. Compared to previous efforts, this algorithm not only enhances the adaptability of coherent signals, but also greatly decreases the complexity. Simulation results indicate the robustness and effectiveness for the proposed algorithm in independent, coherent, and mixed multipath environments and low signal-to-noise ratio (SNR) conditions.

Coordination and Redox Dual-Responsive Mesoporous Organosilica Nanoparticles Amplify Immunogenic Cell Death for Cancer Chemoimmunotherapy.

Amplifying the chemotherapy-driven immunogenic cell death (ICD) for efficient and safe cancer chemoimmunotherapy remains a challenge. Here, a potential ICD nanoamplifier containing diselenide-bridged mesoporous organosilica nanoparticles (MONs) and chemotherapeutic ruthenium compound (KP1339) to achieve cancer chemoimmunotherapy is tailored. KP1339-loaded MONs show controlled drug release profiles via glutathione (GSH)-responsive competitive coordination and matrix degradation. High concentration of MONs selectively evoked reactive oxygen species production, GSH depletion, and endoplasmic reticulum stress in cancer cells, thus amplifying the ICD of KP1339 and boosting robust antitumor immunological responses. After the combination of PD-L1 checkpoint blockade, cancer cell membrane-cloaked KP1339-loaded MONs not only regress primary tumor growth with low systemic toxicity, but also inhibit distant tumor growth and pulmonary metastasis of breast cancer. The results have shown the potential of coordination and redox dual-responsive MONs boosting amplified ICD for cancer chemoimmunotherapy.

A Tumor-Penetrating Nanomedicine Improves the Chemoimmunotherapy of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a low survival rate. The therapeutic effect of chemotherapy and immunotherapy for PDAC is disappointing due to the presence of dense tumor stroma and immunosuppressive cells in the tumor microenvironment (TME). Herein, a tumor-penetrating nanoparticle is reported to modulate the deep microenvironment of PDAC for improved chemoimmunotherapy. The tumor pH-sensitive polymer is synthesized by conjugating N,N-dipentylethyl moieties and monomethoxylpoly(ethylene glycol) onto PAMAM dendrimer, into whose cavity a hydrophobic gemcitabine (Gem) prodrug is accommodated. They self-assemble into nanoparticles (denoted as SPN@Pro-Gem) with the size around 120 nm at neutral pH, but switch into small particles (≈8 nm) at tumor site to facilitate deep delivery of Gem into the tumor parenchyma. In addition to killing cancer cells that resided deeply in the tumor tissue, SPN@Pro-Gem could modulate the TME by reducing the abundance of tumor-associated macrophages and myeloid-derived suppressor cells as well as upregulating the expression level of PD-L1 of tumor cells. This collectively facilitates the infiltration of cytotoxic T cells into the tumors and renders checkpoint inhibitors more effective in previously unresponsive PDAC models. This study reveals a promising strategy for improving the chemoimmunotherapy of pancreatic cancer.

Programmable Delivery of Immune Adjuvant to Tumor-Infiltrating Dendritic Cells for Cancer Immunotherapy.

Tumor-infiltrating dendritic cells (TIDCs) are mostly immature and immunosuppressive, usually mediating immune inhibition. The utilization of cytosine-guanine oligodeoxynucleotides (CpG ODNs) to stimulate the activation of TIDCs has been demonstrated to be effective for improving antitumor immunity. However, a series of biological barriers has limited the efficacy of previous nanocarriers for delivering CpG to TIDCs. Herein, we developed a dual-sensitive dendrimer cluster-based nanoadjuvant for delivering CpG ODNs into TIDCs. We show that the tumor acidity triggers the rapid release of CpG conjugated polyamidoamine (PAMAM) dendrimers from the nanoadjuvant, thus facilitating its perfusion deep into tumors and phagocytosis by TIDCs. Thereafter, the reductive condition of the endolysosomes led to the subsequent release of CpG, which promotes the DCs activation and enhances antitumor immunotherapies. Programmable delivery of immune adjuvant efficiently overcomes the barriers for targeted delivery to TIDCs and provides a promising strategy for improving cancer immunotherapy.

Nanoparticle-Enabled Dual Modulation of Phagocytic Signals to Improve Macrophage-Mediated Cancer Immunotherapy.

Activation of the phagocytosis of macrophages to tumor cells is an attractive strategy for cancer immunotherapy, but the effectiveness is limited by the fact that many tumor cells express an increased level of anti-phagocytic signals (e.g., CD47 molecules) on their surface. To promote phagocytosis of macrophages, a pro-phagocytic nanoparticle (SNPACALR&aCD47 ) that concurrently carries CD47 antibody (aCD47) and a pro-phagocytic molecule calreticulin (CALR) is constructed to simultaneously modulate the phagocytic signals of macrophages. SNPACALR&aCD47 can achieve targeted delivery to tumor cells by specifically binding to the cell-surface CD47 and block the CD47-SIRPα pathway to inhibit the "don't eat me" signal. Tumor cell-targeted delivery increases the exposure of recombinant CALR on the cell surface and stimulates an "eat me" signal. Simultaneous modulation of the two signals enhances the phagocytosis of 4T1 tumor cells by macrophages, which leads to significantly improved anti-tumor efficacy in vivo. The findings demonstrate that the concurrent blockade of anti-phagocytic signals and activation of pro-phagocytic signals can be effective in macrophage-mediated cancer immunotherapy.

BHLHE40 plays a pathological role in pre-eclampsia through upregulating SNX16 by transcriptional inhibition of miR-196a-5p.

Pre-eclampsia (PE), which results from abnormal placentation, is a primary cause of maternal and neonatal morbidity and mortality. However, the causes of abnormal development of the placenta remain poorly understood. BHLHE40 is a transcriptional repressor in response to hypoxia. Bioinformatics analysis demonstrated that BHLHE40 negatively regulates miR-196a-5p expression, which may decrease miR-196a-5p to target SNX16. Since SNX16 exerts an inhibitory effect on cell migration, it may disrupt trophoblast cell migration in placentation. Therefore, the objective of this study was to explore a possible role of the BHLHE40/miR-196a-5p/SNX16 axis in PE pathogenesis. BHLHE40, miR-196a-5p and SNX16 mRNA and/or protein levels were detected in PE and normal placenta tissues. PE models in vitro and in vivo were constructed by culturing trophoblasts under hypoxia and reducing the uterine perfusion pressure in pregnant C57/BL6N mice, respectively. BHLHE40 and SNX16 were upregulated in PE placenta, while miR-196a-5p was downregulated. Knockdown of BHLHE40 reversed miR-196a-5p expression in trophoblasts under hypoxia, and upregulation of miR-196a-5p inhibited SNX16 expression. As indicated by ChIP assay, BHLHE40 bound to the promoter of the miR-196a-5p gene; luciferase reporter analysis showed that miR-196a-5p could bind to the 3'-untranslated region of SNX16 mRNA. Knockdown of either BHLHE40 or SNX16, or an increase in miR-196a-5p, restored cell viability, migration, invasion and matrix metalloprotein (MMP)-2 and MMP-9 expression under hypoxia. BHLHE40 knockdown also alleviated PE symptoms in pregnant C57/BL6N mice. This study supports involvement of the BHLHE40/miR-196a-5p/SNX16 axis in PE pathogenesis; Proper adjustment of the BHLHE40/miR-196a-5p/SNX16 axis is able to attenuate PE symptoms.

Intratumor Performance and Therapeutic Efficacy of PAMAM Dendrimers Carried by Clustered Nanoparticles.

In recent years, small nanoparticles (NPs) with a diameter of less than 10 nm have aroused considerable interest in biomedical applications. However, their intratumor performance, as well as the antitumor efficacy, has not been well understood due to their size-dependent pharmacokinetics, which presents a formidable challenge for delivering a comparable amount of different small NPs to tumor tissues. Utilizing the multistage delivery strategy, we construct G3-, G5-, and G7-iCluster delivery systems by using poly(amidoamine) (PAMAM) dendrimers of different generations (G3-, G5-, and G7-PAMAM) as building blocks. The iCluster nanoparticles showed comparable pharmacokinetics and similar initial tumor deposition due to their similarity in size and surface chemistry. After accumulating at a tumor site, individual small dendrimers were released, and thus, their intratumor performance was comparatively investigated. Our results indicated that a subtle change in generation markedly affects their intratumor activities. G5-iCluster outperformed G3-iCluster and G7-iCluster in the treatment efficacy in an orthotopic pancreatic tumor model. The mechanistic study revealed that G3-PAMAM showed reduced particle retention in tumor tissue due to its small size and weak cell internalization, while G7-PAMAM was much less penetrative because of its relatively large size and strong particle-cell interaction. In contrast, G5-PAMAM exhibited balanced tumor penetration, cell internalization, and tumor retention. Our finding highlights the huge influence of the subtle difference of small NPs in their intratumor performance.

Nanoenabled Reversal of IDO1-Mediated Immunosuppression Synergizes with Immunogenic Chemotherapy for Improved Cancer Therapy.

Certain chemotherapeutics (e.g., oxaliplatin, OXA) can evoke effective antitumor immunity responses by inducing immunogenic cell death (ICD). Unfortunately, tumors always develop multiple immunosuppressive mechanisms, such as the upregulation of immunosuppressive factors, to counteract the effects of immunogenic chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1), a tryptophan catabolic enzyme overexpressed in tumor-draining lymph nodes (TDLNs) and tumor tissues, plays a pivotal role in the generation of the immunosuppressive microenvironment. Reversing IDO1-mediated immunosuppression may strengthen the ICD-induced immune response. Herein, we developed a nanoenabled approach for IDO1 pathway interference, which is accomplished by delivering IDO1 siRNA to both TDLNs and tumor tissues with the help of cationic lipid-assisted nanoparticles (CLANs). We demonstrated that the contemporaneous administration of OXA and CLANsiIDO1 could achieve synergetic antitumor effects via promoting dendritic cell maturation, increasing tumor-infiltrating T lymphocytes and decreasing the number of regulatory T cells in a subcutaneous colorectal tumor model. We further proved that this therapeutic strategy is applicable for the treatment of orthotopic pancreatic tumors and offers a strong immunological memory effect, which can provide protection against tumor rechallenge.

Tumor-Acidity-Cleavable Maleic Acid Amide (TACMAA): A Powerful Tool for Designing Smart Nanoparticles To Overcome Delivery Barriers in Cancer Nanomedicine.

Over the past few decades, cancer nanomedicine has been under intensive development for applications in drug delivery, cancer therapy, and molecular imaging. However, there exist a series of complex biological barriers in the path of a nanomedicine from the site of administration to the site of action. These barriers considerably prevent a nanomedicine from reaching its targets in a sufficient concentration and thus severely limit its therapeutic benefits. According to the delivery process, these biological delivery barriers can be briefly summarized in the following order: blood circulation, tumor accumulation, tumor penetration, cellular internalization, and intracellular drug release. The therapeutic effect of a nanomedicine is strongly determined by its ability to overcome these barriers. However, advances in cancer biology have revealed that each barrier has its own distinct microenvironment, which imposes different requirements on the optimal design of nanocarriers, thus further complicating the delivery process. For example, the pH of blood is neutral, while the tumor extracellular environment features an acidic pH (pHe ≈ 6.5-7.0) and the endosome and lysosome are more acidic (pH 5.5-4.5). The nanoparticles (NPs) should be able to change their properties to adapt to each individual environment for robust and effective delivery. This demand promotes the design and development of smart delivery carriers that can respond to endogenous and exogenous stimuli. It is well-documented that tumors develop acidic extracellular microenvironments with pH ≈ 6.5-7.0 due to their abnormal metabolism in comparison with normal tissues. This provides a unique tool for designing smart NP drug delivery systems. Our studies have revealed that the NPs' physiochemical properties, such as particle size and surface charge, have profound effects on their systemic transport in the body. In different delivery stages, the NPs should possess different sizes or surface charges for optimal performance. We developed a class of stimuli-responsive NPs by incorporating tumor-acidity-cleavable maleic acid amide (TACMAA) as a design feature. TACMAA is produced by the facile reaction of an amino group with 2,3-dimethylmaleic anhydride (DMMA) and its derivatives and can be cleaved under tumor acidity. By virtue of such characteristics, NPs containing TACMAA enable size or surface charge switching at tumor sites so that they can overcome those delivery barriers for improved drug delivery and cancer therapy. In this Account, we systemically review the development and evolution of TACMAA-based delivery systems and elaborate how TACMAA helps the innovation and design of intelligent nanocarriers for overcoming the delivery barriers. In particular, our Account focuses on five parts: TACMAA chemistry, tumor-acidity-triggered charge reversal, tumor-acidity-triggered shell detachment, tumor-acidity-triggered size transition, and tumor-acidity-triggered ligand reactivation. We provide detailed information on how tumor-acidity-triggered property changes correlate with the ability of NPs to overcome delivery barriers.

Stimuli-responsive clustered nanoparticles for improved tumor penetration and therapeutic efficacy.

A principal goal of cancer nanomedicine is to deliver therapeutics effectively to cancer cells within solid tumors. However, there are a series of biological barriers that impede nanomedicine from reaching target cells. Here, we report a stimuli-responsive clustered nanoparticle to systematically overcome these multiple barriers by sequentially responding to the endogenous attributes of the tumor microenvironment. The smart polymeric clustered nanoparticle (iCluster) has an initial size of ∼100 nm, which is favorable for long blood circulation and high propensity of extravasation through tumor vascular fenestrations. Once iCluster accumulates at tumor sites, the intrinsic tumor extracellular acidity would trigger the discharge of platinum prodrug-conjugated poly(amidoamine) dendrimers (diameter ∼5 nm). Such a structural alteration greatly facilitates tumor penetration and cell internalization of the therapeutics. The internalized dendrimer prodrugs are further reduced intracellularly to release cisplatin to kill cancer cells. The superior in vivo antitumor activities of iCluster are validated in varying intractable tumor models including poorly permeable pancreatic cancer, drug-resistant cancer, and metastatic cancer, demonstrating its versatility and broad applicability.

Tumor Acidity/NIR Controlled Interaction of Transformable Nanoparticle with Biological Systems for Cancer Therapy.

Precisely controlling the interaction of nanoparticles with biological systems (nanobio interactions) from the injection site to biological targets shows great potential for biomedical applications. Inspired by the ability of nanoparticles to alter their physicochemical properties according to different stimuli, we explored the tumor acidity and near-infrared (NIR) light activated transformable nanoparticle DATAT-NPIR&DOX. This nanoparticle consists of a tumor acidity-activated TAT [the TAT lysine residues' amines was modified with 2,3-dimethylmaleic anhydride (DA)], a flexible chain polyphosphoester core coencapsulated a NIR dye IR-780, and DOX (doxorubicin). The physicochemical properties of the nanoparticle can be controlled in a stepwise fashion using tumor acidity and NIR light, resulting in adjustable nanobio interactions. The resulting transformable nanoparticle DATAT-NPIR&DOX efficiently avoids the interaction with mononuclear phagocyte system (MPS) ("stealth" state) due to the masking of the TAT peptide during blood circulation. Once it has accumulated in the tumor tissues, DATAT-NPIR&DOX is reactivated by tumor acidity and transformed into the "recognize" state in order to promote interaction with tumor cells and enhance cellular internalization. Then, this nanoparticle is transformed into "attack" state under NIR irradiation, achieving the supersensitive DOX release from the flexible chain polyphosphoester core in order to increase the DOX-DNA interaction. This concept provides new avenues for the creation of transformable drug delivery systems that have the ability to control nanobio interactions.

Spatial Targeting of Tumor-Associated Macrophages and Tumor Cells with a pH-Sensitive Cluster Nanocarrier for Cancer Chemoimmunotherapy.

Chemoimmunotherapy, which combines chemotherapeutics with immune-modulating agents, represents an appealing approach for improving cancer therapy. To optimize its therapeutic efficacy, differentially delivering multiple therapeutic drugs to target cells is desirable. Here we developed an immunostimulatory nanocarrier (denoted as BLZ-945SCNs/Pt) that could spatially target tumor-associated macrophages (TAMs) and tumor cells for cancer chemoimmunotherapy. BLZ-945SCNs/Pt undergo supersensitive structure collapse in the prevascular regions of tumor tissues and enable the simultaneous release of platinum (Pt)-prodrug conjugated small particles and BLZ-945, a small molecule inhibitor of colony stimulating factor 1 receptor (CSF-1R) of TAMs. The released BLZ-945 can be preferentially taken up by TAMs to cause TAMs depletion from tumor tissues, while the small particles carrying Pt-prodrug enable deep tumor penetration as well as intracellularly specific drug release to kill more cancer cells. Our studies demonstrate that BLZ-945SCNs/Pt outperform their monotherapy counterparts in multiple tumor models. The underlying mechanism studies suggest that the designer pH-sensitive codelivery nanocarrier not only induces apoptosis of tumor cells but also modulates the tumor immune environment to eventually augment the antitumor effect of CD8+ cytotoxic T cells through TAMs depletion.

Facile Generation of Tumor-pH-Labile Linkage-Bridged Block Copolymers for Chemotherapeutic Delivery.

Successful bench-to-bedside translation of nanomedicine relies heavily on the development of nanocarriers with superior therapeutic efficacy and high biocompatibility. However, the optimal strategy for improving one aspect often conflicts with the other. Herein, we report a tactic of designing tumor-pH-labile linkage-bridged copolymers of clinically validated poly(D,L-lactide) and poly(ethylene glycol) (PEG-Dlink(m)-PDLLA) for safe and effective drug delivery. Upon arriving at the tumor site, PEG-Dlink(m)-PDLLA nanoparticles will lose the PEG layer and increase zeta potential by responding to tumor acidity, which significantly enhances cellular uptake and improves the in vivo tumor inhibition rate to 78.1% in comparison to 47.8% of the non-responsive control. Furthermore, PEG-Dlink(m)-PDLLA nanoparticles show comparable biocompatibility with the clinically used PEG-b-PDLLA micelle. The improved therapeutic efficacy and safety demonstrate great promise for our strategy in future translational studies.

Ferritin-Based Nanocomposite Hydrogel Promotes Tumor Penetration and Enhances Cancer Chemoimmunotherapy.

Hydrogels are prevailing drug delivery depots to improve antitumor efficacy and reduce systemic toxicity. However, the application of conventional free drug-loaded hydrogel is hindered by poor drug penetration in solid tumors. Here, an injectable ferritin-based nanocomposite hydrogel is constructed to facilitate tumor penetration and improve cancer chemoimmunotherapy. Specifically, doxorubicin-loaded human ferritin (Dox@HFn) and oxidized dextran (Dex-CHO) are used to construct the injectable hydrogel (Dox@HFn Gel) through the formation of pH-sensitive Schiff-base bonds. After peritumoral injection, the Dox@HFn Gel is retained locally for up to three weeks, and released intact Dox@HFn gradually, which can not only facilitate tumor penetration through active transcytosis but also induce immunogenic cell death (ICD) to tumor cells to generate an antitumor immune response. Combining with anti-programmed death-1 antibody (αPD-1), Dox@HFn Gel induces remarkable regression of orthotopic 4T1 breast tumors, further elicits a strong systemic anti-tumor immune response to effectively suppress tumor recurrence and lung metastasis of 4T1 tumors after surgical resection. Besides, the combination of Dox@HFn GelL with anti-CD47 antibody (αCD47) inhibits postsurgical tumor recurrence of aggressive orthotopic glioblastoma tumor model and significantly extends mice survival. This work sheds light on the construction of local hydrogels to potentiate antitumor immune response for improved cancer therapy.

Self-assembled metal-phenolic network nanoparticles for delivery of a cisplatin prodrug for synergistic chemo-immunotherapy.

Despite cisplatin's pivotal role in clinically proven anticancer drugs, its application has been hampered by severe side effects and a grim prognosis. Herein, we devised a glutathione (GSH)-responsive nanoparticle (PFS-NP) that integrates a disulfide bond-based amphiphilic polyphenol (PP-SS-DA), a dopamine-modified cisplatin prodrug (Pt-OH) and iron ions (Fe3+) through coordination reactions between Fe3+ and phenols. After entering cells, the responsively released Pt-OH and disulfide bonds eliminate the intracellular GSH, in turn disrupting the redox homeostasis. Meanwhile, the activated cisplatin elevates the intracellular H2O2 level through cascade reactions. This is further utilized to produce highly toxic hydroxyl radicals (˙OH) catalyzed by the Fe3+-based Fenton reaction. Thus, the amplified oxidative stress leads to immunogenic cell death (ICD), promoting the maturation of dendritic cells (DCs) and ultimately activating the anti-tumor immune system. This innovative cisplatin prodrug nanoparticle approach offers a promising reference for minimizing side effects and optimizing the therapeutic effects of cisplatin-based drugs.

Integrating Bioactive Graded Hydrogel with Radially Aligned Nanofibers to Dynamically Manipulate Wound Healing Process.

Skin wound healing is a complex process that requires appropriate treatment and management. Using a single scaffold to dynamically manipulate angiogenesis, cell migration and proliferation, and tissue reconstruction during skin wound healing is a great challenge. We developed a hybrid scaffold platform that integrates the spatiotemporal delivery of bioactive cues with topographical cues to dynamically manipulate the wound-healing process. The scaffold comprised gelatin methacryloyl hydrogels and electrospun poly(ε-caprolactone)/gelatin nanofibers. The hydrogels had graded cross-linking densities and were loaded with two different functional bioactive peptides. The nanofibers comprised a radially aligned nanofiber array layer and a layer of random fibers. During the early stages of wound healing, the KLTWQELYQLKYKGI peptide, which mimics vascular endothelial growth factor, was released from the inner layer of the hydrogel to accelerate angiogenesis. During the later stages of wound healing, the IKVAVS peptide, which promotes cell migration, synergized with the radially aligned nanofiber membrane to promote cell migration, while the nanofiber membrane also supported further cell proliferation. In an in vivo rat skin wound-healing model, the hybrid scaffold significantly accelerated wound healing and collagen deposition, and the ratio of type I to type III collagen at the wound site resembled that of normal skin. The prepared scaffold dynamically regulated the skin tissue regeneration process in stages to achieve rapid wound repair with clinical application potential, providing a strategy for skin wound repair.

Self-Assembled Nanoparticles from the Amphiphilic Prodrug of Resiquimod for Improved Cancer Immunotherapy.

Tumor-associated macrophages (TAMs) usually adopt a tumor-promoting M2-like phenotype, which largely impedes the immune response and therapeutic efficacy of solid tumors. Repolarizing TAMs from M2 to the antitumor M1 phenotype is crucial for reshaping the tumor immunosuppressive microenvironment (TIME). Herein, we developed self-assembled nanoparticles from the polymeric prodrug of resiquimod (R848) to reprogram the TIME for robust cancer immunotherapy. The polymeric prodrug was constructed by conjugating the R848 derivative to terminal amino groups of the linear dendritic polymer composed of linear poly(ethylene glycol) and lysine dendrimer. The amphiphilic prodrug self-assembled into nanoparticles (PLRS) of around 35 nm with a spherical morphology. PLRS nanoparticles could be internalized by antigen-presenting cells (APCs) in vitro and thus efficiently repolarized macrophages from M2 to M1 and facilitated the maturation of APCs. In addition, PLRS significantly inhibited tumor growth in the 4T1 orthotopic breast cancer model with much lower systemic side effects. Mechanistic studies suggested that PLRS significantly stimulated the TIME by repolarizing TAMs into the M1 phenotype and increased the infiltration of cytotoxic T cells into the tumor. This study provides an effective polymeric prodrug-based strategy to improve the therapeutic efficacy of R848 in cancer immunotherapy.

Intravenous Senescent Erythrocyte Vaccination Modulates Adaptive Immunity and Splenic Complement Production.

Targeted delivery of vaccines to the spleen remains a challenge. Inspired by the erythrophagocytotic process in the spleen, we herein report that intravenous administration of senescent erythrocyte-based vaccines profoundly alters their tropism toward splenic antigen-presenting cells (APCs) for imprinting adaptive immune responses. Compared with subcutaneous inoculation, intravenous vaccination significantly upregulated splenic complement expression in vivo and demonstrated synergistic antibody killing in vitro. Consequently, intravenous senescent erythrocyte vaccination produces potent SARS-CoV-2 antibody-neutralizing effects, with potential protective immune responses. Moreover, the proposed senescent erythrocyte can deliver antigens from resected tumors and adjuvants to splenic APCs, thereby inducing a personalized immune reaction against tumor recurrence after surgery. Hence, our findings suggest that senescent erythrocyte-based vaccines can specifically target splenic APCs and evoke adaptive immunity and complement production, broadening the tools for modulating immunity, helping to understand adaptive response mechanisms to senescent erythrocytes better, and developing improved vaccines against cancer and infectious diseases.