Ultrafast self-gelling polymeric powder with strong wet bioadhesion can be used as effective tissue sealant.

The targeted and simultaneous delivery of diverse cargoes with vastly different properties by the same vehicle is highly appealing but challenging. Here, a bioactive nanocomposite hydrogel based on hyaluronic acid and self‐assembled pamidronate‐magnesium nanoparticles for the localized elution and on‐demand simultaneous release of bioactive ions and small molecule drugs is described. The obtained nanocomposite hydrogels exhibit excellent injectability and efficient stress relaxation, thereby allowing easy injection and consequent adaptation of hydrogels to bone defects with irregular shapes. Magnesium ions released from the hydrogels promote osteogenic differentiation of the encapsulated human mesenchymal stem cells (hMSCs) and activation of alkaline phosphatase (ALP). The activated ALP subsequently catalyzes the dephosphorylation (activation) of Dex phosphate, a pro‐drug of Dex, and expedites the release of Dex from hydrogels to further promote hMSC osteogenesis. This positive feedback circuit governing the activation and release of Dex significantly enhances bone regeneration at the hydrogel implantation sites. The findings suggest that these injectable nanocomposite hydrogels mediate optimized release of diverse therapeutic cargoes and effectively promote in situ bone regeneration via minimally invasive procedures.

Macrophages regulate host responses to implants through their dynamic adhesion, release, and activation. Herein, we employ bisphosphonate (BP)-coated gold nanoparticle template (BNP) to direct the swift and convertible formation of Mg²⁺-functional Mg²⁺-BP nanoparticle (NP) on the BP-AuNP surface via reversible Mg²⁺-BP coordination, thus producing (Mg²⁺-BP)-Au dimer (MgBNP). Ethylenediaminetetraacetic acid-based Mg²⁺ chelation facilitates the dissolution of Mg²⁺-BP NP, thus enabling the reversion of the MgBNP to the BNP. This convertible nanoassembly incorporating cell-adhesive Mg²⁺ moieties directs reversible attachment and detachment of macrophages by BP and EDTA, without physical scraping or trypsin that could damage cells. The swift formation of RGD ligand- and Mg²⁺-bifunctional RGD-Mg²⁺-BP NP that yields (RGD-Mg²⁺-BP)-Au dimer (RGDBNP) further stimulates the adhesion and pro-regenerative M2-type polarization of macrophages, both in vitro and in vivo, including rho-associated protein kinase. This swift and non-toxic dimer formation can include diverse bio-functional moieties to regulate host responses to implants.