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Therapeutics targeting immune checkpoints have achieved astonishing clinical success in cancer treatment. However, these therapies can hardly adapt to immunologically "cold" tumors featuring insufficient and exhausted tumor‐infiltrating lymphocytes as well as low immunogenicity. Herein, a two‐pronged strategy is presented by combining cryo‐shocked M1 macrophages (CSMs) and CD47‐targeted lonidamine nanodrugs (CLNDN) for reprograming the immunosuppressive tumor microenvironment (TME). CSMs induce durable polarization of tumor‐associated macrophages (TAMs) into the immunostimulatory M1 phenotype through the TLR2/MAPK signaling and also elevate CD47 expression in tumor cells, which in turn facilitates the targeted delivery of CLNDN into tumor cells. CLNDN trigger tumor cell‐specific pyroptosis through the caspase‐3/GSDME pathway and lead to the release of damage‐associated molecular patterns. Consequently, the combination of CSM and CLNDN synergistically boosts immune infiltration and tumor cell immunogenicity within the TME, effectively reverting tumor immunosuppression. This combination achieves potent antitumor effects and induces long‐term immune memory against tumor metastasis and recurrence. This work demonstrates for the first time TAM polarization by using cryo‐shocked macrophages and highlights its coordination with tumor pyroptosis for igniting tumor immunity, opening up a new avenue for robust cancer immunotherapy. [ABSTRACT FROM AUTHOR]

In the realm of combined cancer immunotherapy, the strategic combination of therapeutics targeting both cancer cells and macrophages holds immense potential. However, the major challenges remain on how to achieve facile spatiotemporal delivery of these therapies, allowing ease of manipulation and ensuring differential drug release for enhanced synergistic therapeutic effects. In the present study, we introduced a tumor microenvironment (TME)-adapted hydrogel with the phenylboronic acid-modified dipyridamole prodrug (DIPP) as a crosslinker. This prodrug hydrogel scaffold, 3BP@DIPPGel, could be formed in situ by a simple mixture of DIPP and poly(vinyl alcohol) (PVA), and loaded with a high ratio of 3-bromopyruvic acid (3BP). The 3BP@DIPPGel enables spatiotemporal localized delivery of dipyridamole (DIP) and 3BP with distinct release kinetics that effectively reshape the immunosuppressive TME. Upon reactive oxygen species (ROS) stimulation, 3BP@DIPPGel preferentially released 3BP, inducing tumor-specific pyroptosis via the ROS/BAX/caspase-3/GSDME signaling pathway and decreasing the secretion of chemokines such as CCL8 to counteract macrophage recruitment. Subsequently, the crosslinked DIP is released, triggering the tumor-associated macrophages (TAMs) polarization towards the immunostimulatory M1 phenotype via the CCR2/JAK2/STAT3 cascade signaling pathway. This dual action from 3BP@DIPPGel leads to the restoration of tumor cell immunogenicity with high efficacy and activation of immune cells. Furthermore, the 3BP@DIPPGel-based chemoimmunotherapy upregulates the expression of sialic-acid-binding Ig-like lectin 10 and hence sensitizing tumors to anti-CD24 therapy in the tumor-bearing mice. Therefore, this strategy can have significant potential in the prevention of tumor metastases and recurrence. To the best of our understanding, this study represents a pioneering showcase of tumor pyroptosis, induced by glycolytic inhibitors, which can be effectively coordinated with DIP-mediated TAM polarization for immune activation, offering a new paradigm for differentially sustained drug delivery to foster cancer immunotherapy., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2024. Published by Elsevier B.V.)

Scaffolds have garnered considerable attention for enhancing neural repairment for spinal cord injury (SCI) treatment. Both microstructural features and biochemical modifications play pivotal roles in influencing the interaction of cells with the scaffold, thereby affecting tissue regeneration. Here, a scaffold is designed with spiral structure and gradient peptide modification (GS) specifically for SCI treatment. The spiral structure provides crucial support and space, while the gradient peptide isoleucine-lysine-valine-alanine-valine (IKVAV) modification imparts directional guidance for neuronal and axonal extension. GS scaffold shows a significant nerve extension induction effect through its interlayer gap and gradient peptide density to dorsal root ganglia in vitro, while in vivo studies reveal its substantial promotion for functional recovery and neural repair. Additionally, the GS scaffold displays impressive drug-loading capacity, mesenchymal stem cell-derived exosomes can be efficiently loaded into the GS scaffold and delivered to the injury site, thereby synergistically promoting SCI repair. Overall, the GS scaffold can serve as a versatile platform and present a promising multifunctional approach for SCI treatment., (© 2024 Wiley‐VCH GmbH.)

Leukemia is a kind of hematological malignancy originating from bone marrow, which provides essential signals for initiation, progression, and recurrence of leukemia. However, how to specifically deliver drugs to the bone marrow remains elusive. Here, we develop biomimetic vesicles by infusing hematopoietic stem and progenitor cell (HSPC) membrane with liposomes (HSPC liposomes), which migrate to the bone marrow of leukemic mice via hyaluronic acid-CD44 axis. Moreover, the biomimetic vesicles exhibit superior binding affinity to leukemia cells through intercellular cell adhesion molecule-1 (ICAM-1)/integrin β2 (ITGB2) interaction. Further experiments validate that the vesicles carrying chemotherapy drug cytarabine (Ara-C@HSPC-Lipo) markedly inhibit proliferation, induce apoptosis and differentiation of leukemia cells, and decrease number of leukemia stem cells. Mechanically, RNA-seq reveals that Ara-C@HSPC-Lipo treatment induces apoptosis and differentiation and inhibits the oncogenic pathways. Finally, we verify that HSPC liposomes are safe in mice. This study provides a method for targeting bone marrow and treating leukemia., (© 2024. The Author(s).)

The development of minimally invasive surgery has greatly advanced precision tumor surgery, but sometime suffers from restricted visualization of the surgical field, especially during the removal of abdominal tumors. A 3-D inspection of tumors could be achieved by intravenously injecting tumor-selective fluorescent probes, whereas most of which are unable to instantly distinguish tumors via in situ spraying, which is urgently needed in the process of surgery in a convenient manner. In this study, this work has designed an injectable and sprayable fluorescent nanoprobe, termed Poly-g-BAT, to realize rapid tumor imaging in freshly dissected human colorectal tumors and animal models. Mechanistically, the incorporation of γ-glutamyl group facilitates the rapid internalization of Poly-g-BAT, and these internalized nanoprobes can be subsequently activated by intracellular NAD(P)H: quinone oxidoreductase-1 to release near-infrared fluorophores. As a result, Poly-g-BAT can achieve a superior tumor-to-normal ratio (TNR) up to 12.3 and enable a fast visualization (3 min after in situ spraying) of tumor boundaries in the xenograft tumor models, Apc min/+ mice models and fresh human tumor tissues. In addition, Poly-g-BAT is capable of identifying minimal premalignant lesions via intravenous injection., (© 2024 Wiley‐VCH GmbH.)

Rationale: Spinal cord injury (SCI) is an acute damage to the central nervous system that results in severe morbidity and permanent disability. Locally implanted scaffold systems with immobilized mesenchymal stem cells (MSCs) have been widely proven to promote locomotor function recovery in SCI rats; however, the underlying mechanism remains elusive. Methods and Results: In this study, we constructed a hyaluronic acid scaffold system (HA-MSC) to accelerate the adhesive growth of human MSCs and prolong their survival time in SCI rat lesions. MSCs regulate local immune responses by upregulating the expression of anti-inflammatory cytokines. Interestingly, the dramatically increased, but transient expression of interleukin 10 (IL-10) is found to be secreted by MSCs in the first week. Blocking the function of the initially produced IL-10 by the antibody completely abolished the neurological and behavioral recovery of SCI rats, indicating a core role of IL-10 in SCI therapy with HA-MSC implantation. Transcriptome analyses indicated that IL-10 selectively promotes the migration and cytokine secretion-associated programs of MSCs, which in turn helps MSCs exert their anti-inflammatory therapeutic effects. Conclusion: Our findings highlight a novel role of IL-10 in regulating MSC migration and cytokine secretion-associated programs, and determine the vital role of IL-10 in the domination of MSC treatment for spinal cord repair., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)