Refillable nanodrug-capturing systems for extracellular drug delivery and combined cancer therapy

<h2>Summary</h2> Local delivery systems bypass multiple delivery barriers and enhance the therapeutic agent concentration at the desired site via direct injection or post-operative implantation; however, their inability to refill therapeutic agents significantly limits their therapeutic efficacy. To address this issue, a refillable nanodrug-capturing system comprising a β-cyclodextrin (βCD)-modified alginate hydrogel (CdGel) and adamantane (Ad)-decorated nanoparticles (AdNPs) is developed herein. CdGel, locally administered at the disease site, captures and retains systemically injected drug-loaded AdNPs through host-guest interactions, enabling therapeutic agent refilling at the target site. Through the repetitive systemic administration of AdNPs, the refilling capacity of CdGel significantly enhances the anti-metastatic activity of the extracellular-targeted drug batimastat in both orthotopic and post-operative 4T1 breast tumor models. The proposed system facilitates the sequential administration of various drugs for combined cancer therapy and integrates the advantages of local and systemic delivery systems, enabling the enhanced drug accumulation and retention at the desired site.