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We assessed factors that determine the tissue-specific bioactivation of ProTide prodrugs by comparing the disposition and activation of remdesivir (RDV), its methylpropyl and isopropyl ester analogues (MeRDV and IsoRDV, respectively), the oral prodrug GS-621763, and the parent nucleotide GS-441524 (Nuc). RDV and MeRDV yielded more active metabolite remdesivir-triphosphate (RDV-TP) than IsoRDV, GS-621763, and Nuc in human lung cell models due to superior cell permeability and higher susceptivity to cathepsin A. Intravenous administration to mice showed that RDV and MeRDV delivered significantly more RDV-TP to the lung than other compounds. Nevertheless, all four ester prodrugs exhibited very low oral bioavailability (<2%), with Nuc being the predominant metabolite in blood. In conclusion, ProTides prodrugs, such as RDV and MeRDV, are more efficient in delivering active metabolites to the lung than Nuc, driven by high cell permeability and susceptivity to cathepsin A. Optimizing ProTides’ ester structures is an effective strategy for enhancing prodrug activation in the lung.

The cGAS-STING pathway plays a crucial role in innate immune activation against cancer and infections, and STING agonists based on cyclic dinucleotides (CDN) have garnered attention for their potential use in cancer immunotherapy and vaccines. However, the limited drug-like properties of CDN necessitate an efficient delivery system to the immune system. To address these challenges, we developed an immunostimulatory delivery system for STING agonists. Here, we have examined aqueous coordination interactions between CDN and metal ions and report that CDN mixed with Zn2+and Mn2+formed distinctive crystal structures. Further pharmaceutical engineering led to the development of a functional coordination nanoparticle, termed the Zinc–Mn–CDN Particle (ZMCP), produced by a simple aqueous one-pot synthesis. Local or systemic administration of ZMCP exerted robust antitumor efficacy in mice. Importantly, recombinant protein antigens from SARS-CoV-2 can be simply loaded during the aqueous one-pot synthesis. The resulting ZMCP antigens elicited strong cellular and humoral immune responses that neutralized SARS-CoV-2, highlighting ZMCP as a self-adjuvant vaccine platform against COVID-19 and other infectious pathogens. Overall, this work establishes a paradigm for developing translational coordination nanomedicine based on drug–metal ion coordination and broadens the applicability of coordination medicine for the delivery of proteins and other biologics.

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ+and interleukin-10+regulatory T cell populations, and restored ileal abundances of Eggerthellaceaeand Enterorhabdusin allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases.

Systemic administration of immune checkpoint blockade agents can activate the anticancer activity of immune cells; however, the response varies from patient to patient and presents potential off-target toxicities. Local administration of immune checkpoint inhibitors (ICIs) can maximize therapeutic efficacies while reducing side effects. This study demonstrates a minimally invasive strategy to locally deliver anti-programmed cell death protein 1 (anti-PD-1) with shear-thinning biomaterials (STBs). ICI can be injected into tumors when loaded in STBs (STB-ICI) composed of gelatin and silicate nanoplatelets (Laponite). The release of ICI from STB was mainly affected by the Laponite percentage in STBs and pH of the local microenvironment. Low Laponite content and acidic pH can induce ICI release. In a murine melanoma model, the injection of STB-ICI significantly reduced tumor growth and increased CD8+T cell level in peripheral blood. STB-ICI also induced increased levels of tumor-infiltrating CD4+helper T cells, CD8+cytotoxic T cells, and tumor death. The STB-based minimally invasive strategy provides a simple and efficient approach to deliver ICIs locally.

Fabrication of multifunctional scaffolds with biomimicking physical and biological signals play an important role in enhancing tissue regeneration. Multifunctional features come from the composite scaffold with various bioactive molecules. However, simple, biocompatible, and controllable hybridization strategy is still lacking. In this study, we leverage naturally derived extracellular matrix (ECM) as chemically controllable hydrogel carrier to effectively load functional biomolecules. The use of ECM hydrogel takes advantage of both native functionality of ECM components and tunability of hydrogel in controlling release of loaded molecules. As a proof of concept, porous acellular bone scaffold was selected as the solid pristine scaffold to be composited with BMP-2 and VEGF, which are loaded by spinal cord-derived ECM (SC-ECM) hydrogel. Crosslinking degree of SC-ECM hydrogel is tuned by changing genipin concentration, which renders the control over release kinetics of BMP-2 and VEGF. The mechanical strength of scaffold maintained after hybridization and is not significantly decreased in wet condition. In vitroevaluations of scaffolds cocultured with osteoblasts and mesenchymal stem cells (MSCs) demonstrate the biocompatible and bioactive features resulting from the composite scaffolds. Evidenced by alkaline phosphatase test, immunofluorescence, and real-time polymerase chain reaction, differentiation of MSCs towards osteoblast lineage is significantly enhanced by composite scaffolds. Therefore, our strategy in fabricating composite scaffold enabled by biomolecule-loaded ECM hydrogel holds great promise in regenerating diverse tissue types by appropriate combinations of solid pristine scaffolds, ECM, and bioactive molecules.Impact statementWe developed a bioactive molecule (e.g., growth factor, protein) loading method using extracellular matrix hydrogel as a carrier. It brings a new strategy to fabricate composite scaffolds with unique biofunctions.

Immune-cell-derived membranes have garnered significant attention as innovative delivery modalities in cancer immunotherapy for their intrinsic immune-modulating functionalities and superior biocompatibilities. Integrating additional parental cell membranes or synthetic lipid vesicles into cellular vesicles can further potentiate their capacities to perform combinatorial pharmacological activities in activating antitumor immunity, thus providing insights into the potential of hybrid cellular vesicles as versatile delivery vehicles for cancer immunotherapy. Here, we have developed a macrophage-membrane-derived hybrid vesicle that has the dual functions of transporting immunotherapeutic drugs and shaping the polarization of tumor-associated macrophages for cancer immunotherapy. The platform combines M1 macrophage-membrane-derived vesicles with CXCR4-binding-peptide-conjugated liposomes loaded with manganese and doxorubicin. The hybrid nanovesicles exhibited remarkable macrophage-targeting capacity through the CXCR4-binding peptide, resulting in enhanced macrophage polarization to the antitumoral M1 phenotype characterized by proinflammatory cytokine release. The manganese/doxorubicin-loaded hybrid vesicles in the CXCR4-expressing tumor cells evoked potent cancer cytotoxicity, immunogenic cell death of tumor cells, and STING activation. Moreover, cotreatment with manganese and doxorubicin promoted dendritic cell maturation, enabling effective tumor growth inhibition. In murine models of CT26 colon carcinoma and 4T1 breast cancer, intravenous administration of the manganese/doxorubicin-loaded hybrid vesicles elicited robust tumor-suppressing activity at a low dosage without adverse systemic effects. Local administration of hybrid nanovesicles also induced an abscessive effect in a bilateral 4T1 tumor model. This study demonstrates a promising biomimetic manganese/doxorubicin-based hybrid nanovesicle platform for effective cancer immunotherapy tailored to the tumor microenvironment, which may offer an innovative approach to combinatorial immunotherapy.

Nutritional metal ions play critical roles in many important immune processes. Hence, the effective modulation of metal ions may open up new forms of immunotherapy, termed as metalloimmunotherapy. Here, we demonstrate a prototype of cancer metalloimmunotherapy using cyclic dinucleotide (CDN) stimulator of interferon genes (STING) agonists and Mn2+. We screened various metal ions and discovered specific metal ions augmented STING agonist activity, wherein Mn2+promoted a 12- to 77-fold potentiation effect across the prevalent human STING haplotypes. Notably, Mn2+coordinated with CDN STING agonists to self-assemble into a nanoparticle (CDN–Mn2+particle, CMP) that effectively delivered STING agonists to immune cells. The CMP, administered either by local intratumoural or systemic intravenous injection, initiated robust anti-tumour immunity, achieving remarkable therapeutic efficacy with minute doses of STING agonists in multiple murine tumour models. Overall, the CMP offers a new platform for local and systemic cancer treatments, and this work underscores the great potential of coordination nanomedicine for metalloimmunotherapy.

Despite the vital role of vaccines in fighting viral pathogens, effective vaccines are still unavailable for many infectious diseases. The importance of vaccines cannot be overstated during the outbreak of a pandemic, such as the coronavirus disease 2019 (COVID-19) pandemic. The understanding of genomics, structural biology, and innate/adaptive immunity have expanded the toolkits available for current vaccine development. However, sudden outbreaks and the requirement of population-level immunization still pose great challenges in today’s vaccine designs. Well-established vaccine development protocols from previous experiences are in place to guide the pipelines of vaccine development for emerging viral diseases. Nevertheless, vaccine development may follow different paradigms during a pandemic. For example, multiple vaccine candidates must be pushed into clinical trials simultaneously, and manufacturing capability must be scaled up in early stages. Factors from essential features of safety, efficacy, manufacturing, and distributions to administration approaches are taken into consideration based on advances in materials science and engineering technologies. In this review, we present recent advances in vaccine development by focusing on vaccine discovery, formulation, and delivery devices enabled by alternative administration approaches. We hope to shed light on developing better solutions for faster and better vaccine development strategies through the use of biomaterials, biomolecular engineering, nanotechnology, and microfabrication techniques.

The development of 3D printing has significantly advanced the field of bone tissue engineering by enabling the fabrication of scaffolds that faithfully recapitulate desired mechanical properties and architectures. In addition, computer‐based manufacturing relying on patient‐derived medical images permits the fabrication of customized modules in a patient‐specific manner. In addition to conventional 3D fabrication, progress in materials engineering has led to the development of 4D printing, allowing time‐sensitive interventions such as programed therapeutics delivery and modulable mechanical features. Therapeutic interventions established via multi‐dimensional engineering are expected to enhance the development of personalized treatment in various fields, including bone tissue regeneration. Here, recent studies utilizing 3D printed systems for bone tissue regeneration are summarized and advances in 4D printed systems are highlighted. Challenges and perspectives for the future development of multi‐dimensional printed systems toward personalized bone regeneration are also discussed. In the past decade, the development of multi‐dimensional printing has significantly advanced the field of bone tissue engineering by fabricating scaffolds with biomimetic mechanical properties, architectures, and programmable drug release profiles. This review focuses on summarizing recent advances in 3D printed scaffolds, 3D printed drug delivery systems (DDS), and 4D printing strategies for accelerated bone tissue regeneration.

Transdermal delivery of water‐insoluble drugs via hydrogel‐based microneedle (MN) arrays is crucial for improving their therapeutic efficacies. However, direct loading of water‐insoluble drug into hydrophilic matrices remains challenging. Here, a biodegradable MN array patch that is fabricated from naturally derived polymer conjugates of gelatin methacryloyl and β‐cyclodextrin (GelMA‐β‐CD) is reported. When curcumin, an unstable and water‐insoluble anticancer drug, is loaded as a model drug, its stability and solubility are improved due to the formation of an inclusion complex. The polymer‐drug complex GelMA‐β‐CD/CUR can be formulated into MN arrays with sufficient mechanical strength for skin penetration and tunable drug release profile. Anticancer efficacy of released curcumin is observed in three‐dimensional B16F10 melanoma models. The GelMA‐β‐CD/CUR MN exhibits relatively higher therapeutic efficacy through more localized and deeper penetrated manner compared with a control nontransdermal patch. In vivo studies also verify biocompatibility and degradability of the GelMA‐β‐CD MN arrays patch. A hydrogel microneedle (MN) patch based on naturally derived gelatin methacryloyl and β‐cyclodextrin conjugates is developed for transdermal delivery of water‐insoluble drugs. Tunable drug release profiles and enhanced drug stability are demonstrated via curcumin as a model drug. The newly developed MN patch possesses good biocompatibility that can potentially be used for various pharmaceutical applications.

Growth factors (GFs) play a crucial role in directing stem cell behavior and transmitting information between different cell populations for tissue regeneration. However, their utility as therapeutics is limited by their short half‐life within the physiological microenvironment and significant side effects caused by off‐target effects or improper dosage. “Smart” materials that can not only sustain therapeutic delivery over a treatment period but also facilitate on‐demand release upon activation are attracting significant interest in the field of GF delivery for tissue engineering. Three properties are essential in engineering these “smart” materials: 1) the cargo vehicle protects the encapsulated therapeutic; 2) release is targeted to the site of injury; 3) cargo release can be modulated by disease‐specific stimuli. The aim of this review is to summarize the current research on stimuli‐responsive materials as intelligent vehicles for controlled GF delivery; Five main subfields of tissue engineering are discussed: skin, bone and cartilage, muscle, blood vessel, and nerve. Challenges in achieving such “smart” materials and perspectives on future applications of stimuli‐responsive GF delivery for tissue regeneration are also discussed. “Smart” materials that can achieve on demand release of therapeutics in response to biological stimuli on the disease sites attract growing interest in the field of tissue engineering. This review focuses on summarizing recent advances in stimuli‐responsive growth factor release strategies for tissue regeneration with improved efficacy and mitigated side effect.