Triune Nanomodulator Enables Exhausted Cytotoxic T Lymphocyte Rejuvenation for Cancer Epigenetic Immunotherapy.

Oncogene activation and epigenome dysregulation drive tumor initiation and progression, contributing to tumor immune evasion and compromising the clinical response to immunotherapy. Epigenetic immunotherapy represents a promising paradigm in conquering cancer immunosuppression, whereas few relevant drug combination and delivery strategies emerge in the clinic. This study presents a well-designed triune nanomodulator, termed ROCA, which demonstrates robust capabilities in tumor epigenetic modulation and immune microenvironment reprogramming for cancer epigenetic immunotherapy. The nanomodulator is engineered from a nanoscale framework with epigenetic modulation and cascaded catalytic activity, which self-assembles into a nanoaggregate with tumor targeting polypeptide decoration that enables loading of the immunogenic cell death (ICD)-inducing agent. The nanomodulator releases active factors specifically triggered in the tumor microenvironment, represses oncogene expression, and initiates the type 1 T helper (TH1) cell chemokine axis by reversing DNA hypermethylation. This process, together with ICD induction, fundamentally reprograms the tumor microenvironment and significantly enhances the rejuvenation of exhausted cytotoxic T lymphocytes (CTLs, CD8+ T cells), which synergizes with the anti-PD-L1 immune checkpoint blockade and results in a boosted antitumor immune response. Furthermore, this strategy establishes long-term immune memory and effectively prevents orthotopic colon cancer relapse. Therefore, the nanomodulator holds promise as a standalone epigenetic immunotherapy agent or as part of a combination therapy with immune checkpoint inhibitors in preclinical cancer models, broadening the array of combinatorial strategies in cancer immunotherapy.

Engineered Hierarchical Microdevices Enable Pre-Programmed Controlled Release for Postsurgical and Unresectable Cancer Treatment.

Drug treatment is required for both resectable and unresectable cancers to strive for any meaningful improvement in patient outcomes. However, the clinical benefit of receiving conventional systemic administrations is often less than satisfactory. Drug delivery systems are preferable substitutes but still fail to meet diverse clinical demands due to the difficulty in programming drug release profiles. Herein, a microfabrication concept, termed "Hierarchical Multiple Polymers Immobilization" (HMPI), is introduced and biodegradable-polymer-based hierarchical microdevices (HMDs) that can pre-program any desired controlled release profiles are engineered. Based on the first-line medication of pancreatic and breast cancer, controlled release of single gemcitabine and the doxorubicin/paclitaxel combination in situ for multiple courses is implemented, respectively. Preclinical models of postsurgical pancreatic, postsurgical breast, and unresectable breast cancer are established, and the designed HMDs are demonstrated as well-tolerable and effective treatments for inhibiting tumor growth, recurrence, and metastasis. The proposed HMPI strategy allows the creation of tailorable and high-resolution hierarchical microstructures for pre-programming controlled release according to clinical medication schedules, which may provide promising alternative treatments for postsurgical and unresectable tumor control.

Photo-crosslinkable hyaluronic acid microgels with reactive oxygen species scavenging capacity for mesenchymal stem cell encapsulation.

Mesenchymal stem cells (MSCs) have gained increasing attention in various biomedical applications. However, conventional therapeutic approaches, such as direct intravenous injection, are associated with low cell survival due to the shear force during injection and the oxidative stress microenvironments in the lesion area. Herein, a photo-crosslinkable antioxidant hydrogel based on tyramine- and dopamine-modified hyaluronic acid (HA-Tyr/HA-DA) was developed. Meanwhile, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) were encapsulated in HA-Tyr/HA-DA hydrogel using a microfluidic system to create size-controllable microgels (hUC-MSCs@microgels). The HA-Tyr/HA-DA hydrogel was demonstrated to have good rheology, biocompatibility, and antioxidant properties for cell microencapsulation. The hUC-MSCs encapsulated in microgels showed a high viability and a significantly improved the survival rate under oxidative stress conditions. Therefore, the presented work provides a promising platform for MSCs microencapsulation, which may further improve the stem cell-based biomedical applications.

Investigating the Biodegradation Mechanism of Poly(trimethylene carbonate): Macrophage-Mediated Erosion by Secreting Lipase.

Poly(trimethylene carbonate) (PTMC), as one of the representatives of biodegradable aliphatic polycarbonates, has been found to degrade in vivo via surface erosion. This unique degradation behavior and the resulting nonacidic products make it more competitive with aliphatic polyesters (e.g., polylactide) in clinical practice. However, this surface degradation mechanism is complicated and not fully understood to date despite the findings that several reactive oxygen species and enzymes can specifically degrade PTMC in vitro. Herein, the biodegradation mechanism of PTMC was investigated by using possible degradation factors, distinct cell lines, and the inhibitors of these factors. The results demonstrate that PTMC undergoes a specific macrophage-mediated erosion. Macrophages tend to fuse into giant cells and elicit a typical inflammatory response by releasing proinflammatory cytokines. In addition, macrophages are suggested to primarily secrete enzymes (lipase specifically) to erode the PTMC bulk extracellularly as inhibiting their activity effectively prevented this eroding process. The clarification of the biodegradation mechanism in this work suggests that the degradation of PTMC highly depends on the foreign body response. Thus, it reminds the researchers to consider the effect of the microenvironment on the degradation and drug release of PTMC-based implantation devices and localized drug delivery systems.

Effects of Chemical Composition on the Shape Memory Property of Poly(dl-lactide-co-trimethylene carbonate) as Self-Morphing Small-Diameter Vascular Scaffolds.

Smart materials have great potential in many biomedical applications, in which biodegradable shape memory polymers (SMPs) can be used as surgical sutures, implants, and stents. Poly(dl-lactide-co-trimethylene carbonate) (PDLLTC) represents one of the promising SMPs and is widely used in biomedical applications. However, the relationship between its shape memory property and chemical structure has not been fully studied and needs further elaboration. In this work, PDLLTC copolymers in different compositions have been synthesized, and their shape memory properties have been investigated. It has been found that the shape memory property is related to the chemical composition and polymeric chain segments. The copolymer with a DLLA/TMC ratio of 75:25 (PDLLTC7525) has been demonstrated with great shape fixation and recovery ratio at human body temperature. Furthermore, PDLLTC7525-based self-morphing small-diameter vascular scaffolds adhered with inner electrospun aligned gelatin/hyaluronic acid (Gel/HA) nanofibers have been constructed, as a merit of its shape memory property. The scaffolds have been demonstrated to facilitate the proliferation and adhesion of endothelial cells on the inner layer. Therefore, PDLLTC with tailorable shape memory properties represents a promising candidate for the development of SMPs, as well as for small-diameter vascular scaffolds construction.

Biodegradable gemcitabine-loaded microdevice with sustained local drug delivery and improved tumor recurrence inhibition abilities for postoperative pancreatic tumor treatment.

At present, the 10-year survival rate of patients with pancreatic cancer is still less than 4%, mainly due to the high cancer recurrence rate caused by incomplete surgery and lack of effective postoperative adjuvant treatment. Systemic chemotherapy remains the only choice for patients after surgery; however, it is accompanied by off-target effects and server systemic toxicity. Herein, we proposed a biodegradable microdevice for local sustained drug delivery and postoperative pancreatic cancer treatment as an alternative and safe option. Biodegradable poly(l-lactic-co-glycolic acid) (P(L)LGA) was developed as the matrix material, gemcitabine hydrochloride (GEM·HCl) was chosen as the therapeutic drug and polyethylene glycol (PEG) was employed as the drug release-controlled regulator. Through adjusting the amount and molecular weight of PEG, the controllable degradation of matrix and the sustained release of GEM·HCl were obtained, thus overcoming the unstable drug release properties of traditional microdevices. The drug release mechanism of microdevice and the regulating action of PEG were studied in detail. More importantly, in the treatment of the postoperative recurrence model of subcutaneous pancreatic tumor in mice, the microdevice showed effective inhibition of postoperative in situ recurrences of pancreatic tumors with excellent biosafety and minimum systemic toxicity. The microdevice developed in this study provides an option for postoperative adjuvant pancreatic treatment, and greatly broadens the application prospects of traditional chemotherapy drugs.

Bioactive hydrogels based on polysaccharides and peptides for soft tissue wound management.

Due to their inherent and tunable biomechanical and biochemical performances, bioactive hydrogels based on polysaccharides and peptides have shown attractive potential for wound management. In this review, the recent progress of bioactive hydrogels prepared by polysaccharides and peptides for soft tissue wound management is overviewed. Meanwhile, we focus on the elaboration of the relationship between chemical structures and inherent bioactive functions of polysaccharides and peptides, as well as the strategies that are taken for achieving multiple wound repairing effects including hemostasis, adhesion, wound contraction and closure, anti-bacteria, anti-oxidation, immunomodulation, molecule delivery, etc. Some innovative and important works are well introduced as well. In the end, current study limitations, clinical unmet needs, and future directions are discussed.

Multifunctional polysaccharide hydrogels for skin wound healing prepared by photoinitiator-free crosslinking.

Photocrosslinked hydrogels show great potential as dressings for skin wound healing. However, most current hydrogels suffer from poor adhesion, toxic photoinitiators, and insufficient versatility. Therefore, developing novel hydrogel dressings with appropriate properties is of great importance to accelerate the wound healing process. In this study, we developed a polysaccharide-based dual-network hydrogel consisting of azide-functionalized carboxymethyl chitosan and o-nitrobenzyl-modified hyaluronic acid (CMC-AZ/HA-NB). The hydrogel showed excellent mechanical, tissue adhesion, and water retention properties. Controllable in situ photocrosslinking was carried out without photoinitiator, avoiding issues associated with the cytotoxicity of photoinitiators. An antibacterial agent-loaded hydrogel (CMC-AZ/HA-NB@D) showed enhanced antibacterial properties. In addition, the CMC-AZ/HA-NB@D hydrogel promoted collagen deposition and vascular formation, as well as reducing the expression of pro-inflammatory factors, thereby accelerating the wound healing process and improving skin regeneration. The present results highlight the promising potential of multifunctional photoinitiator-free polysaccharide hydrogels for application in wound dressings.

L-Arg-Rich Amphiphilic Dendritic Peptide as a Versatile NO Donor for NO/Photodynamic Synergistic Treatment of Bacterial Infections and Promoting Wound Healing.

The development of alternative strategies for the efficient treatment of subcutaneous abscesses that do not require the massive use of antibiotics and surgical intervention is urgently needed. Herein, a novel synergistic antibacterial strategy based on photodynamic (PDT) and NO gas therapy is reported, in which, a PDT-driven NO controllable generation system (Ce6@Arg-ADP) is developed with l-Arg-rich amphiphilic dendritic peptide (Arg-ADP) as a carrier. This carrier not only displays superior bacterial association and biofilm penetration performance, but also acts as a versatile NO donor. Following efficient penetration into the interior of the biofilms, Ce6@Arg-ADP can rapidly produce massive NO via utilizing the H2 O2 generated during PDT to oxidize Arg-ADP to NO and l-citrulline, without affecting singlet oxygen (1 O2 ) production. The combination of 1 O2 and the reactive by-products of NO offers notable synergistic antibacterial and biofilm eradication effects. Importantly, following efficient elimination of all bacteria from the abscess site, Arg-ADP can further generate trace quantities of NO to facilitate the angiogenesis and epithelialization of the wound tissues, thereby notably promotes wound healing. Together, this study clearly suggests that Arg-ADP is a versatile NO donor, and the combination of PDT and NO represents a promising strategy for the efficient treatment of subcutaneous abscesses.

A versatile chitosan nanogel capable of generating AgNPs in-situ and long-acting slow-release of Ag+ for highly efficient antibacterial.

Development of multifunctional antibacterial agent with long-lasting antibacterial activity and biofilm ablation performance is significant for the effective treatment of bacterial infections. Here, by utilizing the electrostatic interaction between sulfonated chitosan (SCS) and Ag+ and chitosan (CS), and the sodium borohydride reduction method, a versatile antibacterial agent (AgNPs@CS/SCS) capable of generating silver nanoparticles (AgNPs) in-situ and long-acting slow-release Ag+ was developed. AgNPs@CS/SCS has a good physiological stability and can long-acting slow-release of Ag+ due to the pH-dependent Ag+ release behavior of AgNPs. Noteworthy, AgNPs@CS/SCS can exert both excellent short- and long-term antibacterial and biofilm ablation activity. Importantly, it also exhibits superior antibacterial activity in the treatment of implant infections, accompanied by good biocompatibility. Together, this study suggest that AgNPs@CS/CSC is indeed a versatile antibacterial agent, and is expected to provide an effective treatment modality for implant infections in the clinic settings.

An Alternating Irradiation Strategy-Driven Combination Therapy of PDT and RNAi for Highly Efficient Inhibition of Tumor Growth and Metastasis.

Hypoxia and hypoxia induced overexpression of vascular endothelial growth factor (VEGF) not only seriously affects the treatment effects of photodynamic therapy (PDT) but also promotes tumor metastasis. Herein, an alternating irradiation strategy (referred to as alternate use of low/high dose of light [ALHDL] irradiation)-driven combination therapy of PDT and RNA interference (RNAi) is developed to synergistically inhibit tumor growth and metastasis. A cationic amphipathic peptide (ALS) served as a carrier in the co-delivery system of photochlor (HPPH) and siVEGF (ALSH/siVEGF). At the beginning of ALHDL-driven ALSH/siVEGF treatment, short-term LDL irradiation can facilitate the tumor penetration, cellular uptake, and endosome escape of ALSH/siVEGF. Moreover, accompanied by HDL-mediated rapid cell apoptosis and LDL-mediated efficient VEGF silencing, the joint use of PDT and RNAi achieved remarkable antitumor effects both in vitro and in vivo. Importantly, benefited from the excellent performance of ALHDL in slowing the rapid deterioration of the anoxic environment of tumors, and ALSH/siVEGF treatment-mediated highly improved VEGF silencing efficacy and inhibitory effect on angiogenesis, the liver and lung metastases of HeLa cells have been successfully suppressed. Together, this study clearly indicates that ALHDL-driven combination therapy of PDT and RNAi is a highly effective modality for inhibition of tumor growth and metastasis.

A multifunctional anti-inflammatory drug that can specifically target activated macrophages, massively deplete intracellular H2O2, and produce large amounts CO for a highly efficient treatment of osteoarthritis.

Specifically inhibiting the proliferation of activated macrophages and clearing the high levels of reactive oxygen species (ROS) secreted by macrophages is crucial for osteoarthritis (OA) treatment. Moreover, if the clearance of these high levels of ROS can be simultaneously used to induce oxidation-responsive release of anti-inflammatory drugs, the therapeutic effect of OA may be further improved. Here, a multifunctional anti-inflammatory drug (CPHs) based on a peptide dendrimer nanogel was constructed by physically encapsulating CORM-401 and wrapping its surface with folic acid (FA)-modified hyaluronic acid (HA). CPHs is capable of efficiently entering activated macrophages via FA- and HA-mediated specific targeting effects and then rapidly release large amounts of CO by massive consumption of H2O2. The generated CO effectively suppresses the secretion of interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α by inhibiting cell proliferation; inducing the activation of heme oxygenase (HO-1), and downregulating the expression of p38 MAPK, NF-kB (p50/p65) and TLR-2. In vivo experiments further confirmed that CPHs can massively deplete ROS in OA joints and effectively suppress the degradation of articular cartilage and their extracellular matrix. More importantly, CPHs is non-toxic to normal macrophages, and the high levels of CO generated in the joints do not result in notable changes in the HbCO levels in blood. Together, these results show that CPHs is an effective and safe anti-inflammatory drug and has essential application prospects in OA treatment.

Ultra-efficient Antibacterial System Based on Photodynamic Therapy and CO Gas Therapy for Synergistic Antibacterial and Ablation Biofilms.

In recent years, with the emergence of various kinds of drug-resistant bacteria, existing antibiotics have become inefficient in killing these bacteria, and the formation of biofilms has further weakened the therapeutic effect. More problematically, the massive use and abuse of antibiotics have caused severe side effects. Thus, the development of ultra-efficient and safe antibacterial systems is urgently needed. Herein, a photodynamic therapy (PDT)-driven CO-controlled delivery system (Ce6&CO@FADP) is developed for synergistic antibacterial and ablation biofilms. Ce6&CO@FADP is constructed using a fluorinated amphiphilic dendritic peptide (FADP) and physically loaded with Ce6 and CORM-401. After efficiently entering the bacteria, Ce6&CO@FADP can rapidly release CO intracellularly by the massive consumption of the H2O2 generated during the PDT process, without affecting the generation of singlet oxygen (1O2). As such, the combination of CO and 1O2 exerts notable synergistic antibacterial and biofilm ablation effects both in vitro and in vivo (including subcutaneous bacterial infection and biofilm catheter models) experiments. More importantly, all biosafety assessments suggest the good biocompatibility of Ce6&CO@FADP. Together, these results reveal that Ce6&CO@FADP is an efficient and safe antibacterial system, which has essential application prospects for the treatment of bacterial infections and ablation of biofilms in vivo.

Tumor-pH-Sensitive PLLA-Based Microsphere with Acid Cleavable Acetal Bonds on the Backbone for Efficient Localized Chemotherapy.

Nanoparticle- and microsphere-based drug delivery systems (DDSs) have attracted wide attention in cancer therapy; those DDSs that are responsive to tumor environment can selectively identify tumor and normal tissues and therefore have shown enhanced anticancer efficacy and alleviated systemic toxicity. Here, tumor-pH-sensitive polymeric microspheres, which are prepared by multiblock poly(l-lactide) with pH-sensitive acetal bonds in the backbone, are employed to efficiently load water-soluble anticancer drug doxorubicin hydrochloride (DOX·HCl, drug loading content: ∼10%). The pH-sensitive DOX-loaded hollow microspheres were in the size range 2-10 µm and exhibited acid-accelerated degradation of polymer matrix and drug release, and thereby efficient in vitro cancer cell inhibition. The microspheres were further intratumorally injected into breast-tumor-bearing mice, and the in vivo anticancer experiment showed that pH-sensitive DOX-loaded microsphere showed better antitumor efficiency and prolonged life-span than its counterpart that does not have pH-responsive property. Moreover, negligible organ toxicity, especially cardiotoxicity that generally exists in DOX-involved chemotherapy where DOX is administrated by intravenous injection, was observed for DOX-loaded microspheres. Hence, tumor-pH-sensitive polymeric microspheres have appeared to be a simple and efficient platform for delivering hydrophilic anticancer drug with excellent anticancer efficacy and low systemic toxicity.

A facile one-step gelation approach simultaneously combining physical and chemical cross-linking for the preparation of injectable hydrogels.

Injectable hydrogels are promising substrates for tissue engineering and drug delivery applications, while the existing hydrogels and gelation approaches usually have unsatisfactory mechanical strength, notable cytotoxicity, limited controllability, and complex and time-consuming gelation process. Herein, an ultra-facile and versatile approach is reported to overcome these problems via a simultaneously occurring physical (hydrogen bond and π-π stacking) and chemical (transesterification) cross-linking between the polyamidoamine (PAMAM) and N-hydroxysuccinimide/maleimide dual-functionalized PEG (NHS-PEG-MAL). Because of skillfully integrated major advantages of individual physical and chemical cross-linking, as well as due to the simplification of the complex and time-consuming gelation process of sequential multi-step cross-linking, this approach displays various advantages over traditional ones, including excellent mechanical strength, good homogeneity and plasticity, good controllability in gelation rate (tens of seconds to several minutes), porosity and storage modulus (several kPa to several MPa). Moreover, this approach demonstrates a relatively gentle and safe gelation process accompanied by favorable biocompatibility for 3D cell culture. The cell viability of all the resultant hydrogels is >80% after culturing for 2 days, which even increases to >90% for 10% w/v hydrogels. Taken together, this study reports an ultra-facile and versatile approach for the preparation of injectable hydrogels with numerous advanced features enabling various biomedical applications.