Magnetically actuated aggregation of nanoparticles via host–guest interaction for extracellular targeted drug delivery and cancer immunotherapy

Rational design of nanomedicine can efficiently improve the therapeutic activity of anticancer drugs; however, the current design strategies are to increase the concentration of drugs within targeted cells, which is not applicable to extracellular-targeted drugs. Herein, we report a nanoparticular aggregation strategy via magnetic actuation and host–guest interaction for extracellular drug delivery. The β-cyclodextrin (βCD)-decorated magnetic nanoparticles (βCD-MNPs) were first administrated and infiltrated into tumor tissue under the magnetic actuation, and then generated mild hyperthermia under alternating magnetic field (AMF) to improve the infiltration of another adamantane (Ad)-decorated NPs (Ad-NPs) into the tumor tissue. Subsequently, the βCD-MNP and Ad-NP would form micro-sized aggregation via the host–guest interaction, which could significantly enhance the enrichment and retention of extracellular-targeted drugs and also minimize their cellular uptake. This nanoparticular aggregation strategy remarkably improved the therapeutic activity of batimastat and PD-1/PD-L1 inhibitor 1 (BMS-1), both of which were extracellular-targeted drug. Such nanoparticular aggregation strategy represents a rational avenue for extracellular drug delivery.