RBC-hitchhiking regime is shown without prolongation of nanoparticle blood circulation but with the record 120-fold boost of particle delivery to lungs. The approach is efficient for treatment of pulmonary metastases.

Smart materials that can switch between different states under the influence of chemical triggers are highly demanded in biomedicine, where specific responsiveness to biomarkers is imperative for precise diagnostics and therapy. Superior selectivity of drug delivery to malignant cells may be achieved with the nanoagents that stay “inert” until “activation” by the characteristic profile of microenvironment cues (e.g., tumor metabolites, angiogenesis factors, microRNA/DNA, etc.). However, despite a wide variety and functional complexity of smart material designs, their real-life applications are hindered by very limited sensitivity to inputs. Here, we present ultrasensitive smart nanoagents with input-dependent On/Off switchable affinity to a biomedical target based on a combination of gold nanoparticles with low-energy polymer structures. In the proposed method, a nanoparticle-based agent is surface coated with a custom designed flexible polymer chain, which has an input-switchable structure that regulates accessibility of the terminal receptor for target binding. Implementation of the concept with a DNA-model of such polymer has yielded nanoagents that have input-dependent cell-targeting capabilities and responsiveness to as little as 30 fM of DNA input in 15 min lateral flow assay. Thus, we show that surface phenomena can augment nanoagents with capability for switchable affinity without compromising the sensitivity to inputs. The proposed approach is promising for development of next-generation theranostic agents and ultrasensitive nanosensors for point-of-care diagnostics.

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