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.

Convincing evidence indicates that the existence of cancer stem cells (CSCs) within malignant tumors is mostly responsible for the failure of chemotherapy. Therefore, instead of merely targeting bulk cancer cells, simultaneous elimination of both CSCs and bulk cancer cells is necessary to improve therapeutic outcomes. Herein, we designed cationic-lipid-assisted nanoparticles ^DTXLNP_siRNA for simultaneous encapsulation of the conventional chemotherapeutic agentdocetaxel (DTXL) and small interfering RNA (siRNA) targeting BMI-1 (siBMI-1). We confirmed that nanoparticles ^DTXLNP_siBMI-1 effectively deliver both therapeutic agents into CSCs and bulk cancer cells. The bulk cancer cells were effectively killed by the DTXL encapsulated in ^DTXLNP_siBMI-1. In breast CSCs, BMI-1 expression was significantly downregulated by ^DTXLNP_siBMI-1; consequently, the stemness was reduced and chemosensitivity of CSCs to DTXL was enhanced, resulting in the elimination of CSCs. Therefore, via ^DTXLNP_siBMI-1, the combination of siBMI-1 and DTXL completely inhibited tumor growth and prevented a relapse by synergistic killing of CSCs and bulk cancer cells in a murine model of an MDA-MB-231 orthotropic tumor.