The functional reconstruction of bone defects caused by trauma, infection, surgical resection and degenerative diseases poses substantial clinical challenges. Bone tissue engineering (BTE) holds immense potential for treating bone defects while avoiding complications commonly associated with conventional autografts, allografts and internal fixation. Bioactive hydrogels with exceptional drug delivery capabilities, excellent biocompatibility and tunable physicochemical properties have emerged as promising biomaterial scaffolds for BTE. This review provides a comprehensive overview of recent advancements in bioactive hydrogel–based strategies for BTE applications. An initial introduction to bone physiology is followed by a critical discussion of the design considerations for hydrogel platforms, specifically biomaterial selection, innovative crosslinking mechanisms and bioactive functionalization. Furthermore, hydrogel engineering for the controlled delivery of bioactive cargo is critically examined, with an emphasis on spatiotemporally programmable release behaviors that coordinate osteogenesis, angiogenesis and immunomodulation. Finally, key translational challenges are discussed, and the emerging role of artificial intelligence–assisted design is explored as a transformative approach for facilitating the clinical translation of next-generation bioactive hydrogels for BTE.
Therapeutic monoclonal antibodies have revolutionized the treatment of cancers, infectious diseases and immune disorders; however, their efficacy is compromised by limitations associated with systemic administration, including systemic toxicity, poor patient compliance and inadequate drug concentration at pathological sites. Hydrogels are promising carriers for localized antibody delivery, but conventional formulations fail to simultaneously address the dual challenges of uncontrolled antibody release and insufficient hydrogel retention at the target site. Herein, leveraging a peptide co-assembly strategy, we engineered an injectable dual-affinity self-assembling peptide hydrogel for localized antibody delivery. This hydrogel integrates three components: peptide FEK as the hydrogel matrix, MEP-FEK incorporating 4-mercaptoethylpyridine (MEP) for non-covalent antibody binding, and C1BP-FEK functionalized with the collagen-binding peptide TKKTLRT for tumor extracellular matrix anchoring. The dual-affinity hydrogel enabled controlled antibody release, exhibiting only 40% cumulative release by Day 90 and an 8.8-fold reduction in initial diffusion rate. In proof-of-concept studies using SKOV3 tumor-bearing mice, the hydrogel carrying trastuzumab as a model therapeutic antibody enhanced local antibody retention, reduced. systemic exposure, exhibited negligible toxicity, and achieved a tumor inhibition rate of 68% This dual-affinity strategy overcomes limitations of conventional affinity-based hydrogels, providing a biocompatible and versatile platform for localized antibody therapy in oncology and other biomedical applications.
The stimulator of interferon genes (STING) pathway plays a critical role in bridging innate and adaptive antitumor immunity, representing a promising target in cancer immunotherapy. However, the clinical application of STING agonists is limited by poor pharmacokinetics, low cytosolic delivery efficiency, and immune-related adverse effects. To address these challenges, we developed STING polyproagonist nanoparticles (named GA+S@SR) by self-assembly of an amphiphilic diblock copolymer, P(OEGMA-co-GAMA)-b-PSSRMA, combined with POEGMA-b-P(DEAEMA-co-BMA). The galactose (GA) moieties enable targeted delivery to glucose transporter 1 (GLUT1) on tumor cells, facilitating cellular internalization. The P(DEAEMA-co-BMA) segments promote endosomal escape, followed by the release of the disulfide-linked SR-717 in the cytosol under reducing conditions. This leads to robust activation of the STING pathway, resulting in dendritic cell maturation, enhanced T-cell infiltration, and potent antitumor immunity. Furthermore, when combined with an αPD-L1, this polyproagonist synergistically enhances the efficacy of immune checkpoint blockade, effectively inhibiting primary and distant tumors by counteracting immune evasion. This study highlights the potential of STING polyproagonists in achieving effective cytosolic delivery of STING agonists to boost antitumor immunity and overcome current limitations associated with STING immunotherapy.
With low five-year survival estimates, poor prognosis, and high recurrence probabilities, glioma is considered one of the most intractable malignant tumors. Despite the discovery of lymphatic vascular system and immune system in the central nervous system (CNS), immune checkpoint blockade therapeutics, such as programmed death ligand 1 (PDL1, also called B7H1 or CD274) antibodies, are prevented from the CNS and glioma sites due to the existence of biological barriers including the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB). Herein, we constructed a BBB/BBTB-crossing recombinant antibody by fusing the PDL1 antibody (αPDL1) and the targeting moiety RAP22 peptide (RAP22) through a matrix metalloproteinase 2 (MMP2)-responsive cleavable linker, abbreviated as αPDL1-mRAP22. Not only was αPDL1-mRAP22 able to block PD1/PDL1 pathway, reduce T cell apoptosis, enhance T cell killing ability towards glioma cells in vitro, but also it showed higher accumulation in the glioma site, prolonged survival time, and potent immune responses as well as synergistic effects with temozolomide (TMZ) in vivo, offering a novel strategy for glioma immunotherapy.
