Delivery of small interfering RNA (siRNA) by nanocarriers has shown promising therapeutic potential in cancer therapy. However, poor understanding of the correlation between the physicochemical properties of nanocarriers and their interactions with biological systems has significantly hindered its anticancer efficacy. Herein, in order to identify the optimal size of nanocarriers for siRNA delivery, different sized cationic micellar nanoparticles (MNPs) (40, 90, 130, and 180 nm) are developed that exhibit similar siRNA binding efficacies, shapes, surface charges, and surface chemistries (PEGylation) to ensure size is the only variable. Size-dependent biological effects are carefully and comprehensively evaluated through both in vitro and in vivo experiments. Among these nanocarriers, the 90 nm MNPs show the optimal balance of prolonged circulation and cellular uptake by tumor cells, which result in the highest retention in tumor cells. In contrast, larger MNPs are rapidly cleared from the circulation and smaller MNPs are inefficiently taken up by tumor cells. Accordingly, 90 nm MNPs carrying polo-like kinase 1 (Plk1)-specific siRNA (siPlk1) show superior antitumor efficacy, indicating that 90 nm could either be the optimal size for systemic delivery of siRNA or close to it. Our findings provide valuable information for rationally designing nanocarriers for siRNA-based cancer therapy in the future.

Patients with Her2-overexpressing (Her2⁺) breast cancers generally have a poorer prognosis due to the high aggressiveness and chemoresistance of the disease. Small interfering RNA (siRNA) targeting the gene encoding polo-like kinase 1 (Plk1; siPlk1) has emerged as an efficient therapeutic agent for Her2⁺ breast cancers. Poly(ethylene glycol)-block-poly(d,l-lactide) (PEG-PLA)-based nanoparticles for siRNA delivery were previously developed and optimized. In this study, for targeted delivery of siPlk1 to Her2⁺ breast cancer, anti-Her2 single-chain variable fragment antibody (ScFv_Her2)-decorated PEG-PLA-based nanoparticles with si Plk1 encapsulation (ScFv_Her2-NP_{si Plk1}) are developed. With the rationally designed conjugation site, ScFv_Her2-NP_siRNA can specifically bind to the Her2 antigen overexpressed on the surface of Her2⁺ breast cancer cells. Therefore, ScFv_Her2-NP_{si Plk1} exhibits improved cellular uptake, promoted Plk1 silencing efficiency, and induced enhanced tumor cell apoptosis in Her2⁺ breast cancer cells, when compared with nontargeted NP_{si Plk1}. More importantly, ScFv_Her2-NP_siRNA markedly enhances the accumulation of siRNA in Her2⁺ breast tumor tissue, and remarkably improves the efficacy of tumor suppression. Dose-dependent anti-tumor efficacy further demonstrates that ScFv_Her2-decorated PEG-PLA-based nanoparticles with siPlk1 encapsulation can significantly enhance the inhibition of Her2⁺ breast tumor growth and reduce the dose of injected siRNA. These results suggest that ScFv_Her2-decorated PEG-PLA-based nanoparticles show great potential for targeted RNA interference therapy of Her2⁺ breast tumor.

Inspired by the influence of chemical structure of end groups on the phase transition temperature of thermoresponsive polymers, we demonstrated a strategy to control the multi-responsiveness of polymer assemblies via subtle modification of end groups of thermoresponsive polymer segments and revealed its potential application for drug delivery. By developing polymer assemblies composed of poly(aliphatic ester) as the inner core and thermoresponsive polyphosphoester as the outer shell, we showed that end groups of thermoresponsive polyphosphoester segments controlled the surface property of assemblies and further determined the stimuli-responsive behavior. The phase-transition temperatures of the unmodified polymer assemblies are tightly controlled by their surface properties due to the hydrophilic to hydrophobic transitions of end groups in response to an environmental stimulus (e.g. pH or light irradiation). External control over these surface properties can by asserted by adjusting the chemical structure and composition of the terminal groups of the thermoresponsive polyphosphoesters.