Tissue repair represents a highly intricate and ordered dynamic process, critically reliant on the orchestration of immune cells. Among these, neutrophils, the most abundant leukocytes in the body, emerge as the initial immune responders at injury sites. Traditionally recognized for their antimicrobial functions in innate immunity, neutrophils now garner attention for their indispensable roles in tissue repair. This review delves into their novel functions during the early stages of tissue injury. We elucidate the mechanisms underlying neutrophil recruitment and activation following tissue damage and explore their contributions to vascular network formation. Furthermore, we investigate the pivotal role of neutrophils during the initial phase of repair across different tissue types. Of particular interest is the investigation into how the fate of neutrophils influences overall tissue healing outcomes. By shedding light on these emerging aspects of neutrophil function in tissue repair, this review aims to pave the way for novel strategies and approaches in future organ defect repair, regeneration studies, and advancements in tissue engineering. The insights provided here have the potential to significantly impact the field of tissue repair and regeneration.

The reconstruction of bone defects has been associated with severe challenges worldwide. Nowadays, bone marrow mesenchymal stem cell (BMSC)-based cell sheets have rendered this approach a promising way to facilitate osteogenic regeneration in vivo. Extracellular vesicles (EVs) play an essential role in intercellular communication and execution of various biological functions and are often employed as an ideal natural endogenous nanomedicine for restoring the structure and functions of damaged tissues. The perception of polymorphonuclear leukocytes (neutrophils, PMNs) as indiscriminate killer cells is gradually changing, with new evidence suggesting a role for these cells in tissue repair and regeneration, particularly in the context of bone healing. However, the role of EVs derived from PMNs (PMN-EVs) in bone regeneration remains largely unknown, with limited research being conducted on this aspect. In the current study, we investigated the effects of PMN-EVs on BMSCs and the underlying molecular mechanisms as well as the potential application of PMN-EVs in bone regeneration. Toward this end, BMSC-based cell sheets with integrated PMN-EVs (BS@PMN-EVs) were developed for bone defect regeneration. PMN-EVs were found to significantly enhance the proliferation and osteogenic differentiation of BMSCs in vitro. Furthermore, BS@PMN-EVs were found to significantly accelerate bone regeneration in vivo by enhancing the maturation of the newly formed bone in rat calvarial defects; this is likely attributable to the effect of PMN-EVs in promoting the expression of key osteogenic proteins such as SOD2 and GJA1 in BMSCs. In conclusion, our findings demonstrate the crucial role of PMN-EVs in promoting the osteogenic differentiation of BMSCs during bone regeneration. Furthermore, this study proposes a novel strategy for enhancing bone repair and regeneration via the integration of PMN-EVs with BMSC-based cell sheets.

Dual blockade of the PD-1/PD-L1 axis, enabling tumor immune evasion, and the VEGF pathway, driving immunosuppression, represents a promising cancer immunotherapy strategy. Combining immune checkpoint inhibitors (ICIs) with antiangiogenics faces toxicity and cost limitations. Bispecific antibodies (BsAbs) targeting both pathways offer a solution. Preclinical and clinical studies demonstrate that simultaneous inhibition enhances antitumor immunity by reversing T-cell exhaustion, normalizing vasculature, and countering immunosuppression. Ivonescimab, a first-in-class PD-1/VEGF BsAb, exemplifies this approach. Approved in China (NMPA, May 2024) for EGFR-mutant non-squamous NSCLC post-TKI failure and included in national insurance (November 2024), it is under global evaluation in solid tumors. PD-1(L1)/VEGF BsAbs like ivonescimab represent a novel therapeutic strategy with potential for improved efficacy and mitigated toxicity compared to combination therapies. Ongoing trials will define broader applications.