Theranostic size-reducible and no donor conjugated gold nanocluster fabricated hyaluronic acid nanoparticle with optimal size for combinational treatment of breast cancer and lung metastasis

The size of nanoparticles plays a key role in utilizing enhanced permeability and retention (EPR) effect of tumor, where large-sized nanoparticles possess good retention but poor penetration, while small-sized nanoparticles are on the contrary. Although size-reducible nanoparticles have been designed to partially overcome this dilemma, the initial size and complicated tumor microenvironment remain restricting the tumor distribution of nanoparticles. Herein, we employed tumor-specific CD44 targeted, hyaluronidase-degradable hyaluronic acid (HA) and small-sized, renal-clearable, red emission, cationic bovine serum albumin-protected gold nanocluster ( [email protected] ) to successfully construct size-reducible nanoplatform ( [email protected] @HA). By changing the ratio of HA and [email protected] , different initial sizes of [email protected] @HA were prepared and their tumor targeting efficiencies, pharmacokinetic profiles were evaluated. Then 200  nm of [email protected] @HA with optimal EPR effect was screened out to further load paclitaxel (PTX) and indocyanine green (ICG) for chemo- photothermal therapy and nitric oxide (NO) for modulating tumor microenvironment and enhancing drug delivery. The [email protected] @HA-NO 3 showed size-reducible ability under triggering by hyaluronidase and high accumulation in breast cancer with homogenous intra-tumor distribution, suppressed 95.3% of in-situ tumor growth and inhibited 88.4% of lung metastasis growth. In conclusion, we provide a strategy that fully satisfied the concerns in drug delivery to tumor for improved antitumor effect.