Space Station-like Composite Nanoparticles for Co-Delivery of Multiple Natural Compounds from Chinese Medicine and Hydrogen in Combating Sensorineural Hearing Loss

Ototoxic drugs such as aminoglycoside antibiotics andcisplatin(CDDP) can cause sensorineural hearing loss (SNHL), which is closelyrelated to oxidative stress and the acidification of the inner earmicroenvironment. Effective treatment of SNHL often requires multifacetedapproach due to the complex pathology, and drug combination therapyis expected to be at the forefront of modern hearing loss treatment.Here, space-station-like composite nanoparticles (CCC@mPP NPs) withpH/oxidation dual responsiveness and multidrug simultaneous deliverycapability were constructed and then loaded with various drugs includingpanax notoginseng saponins (PNS), tanshinone IIA (TSIIA), and ammoniaborane (AB) to provide robust protection against SNHL. Molecular dynamicssimulation revealed that carboxymethyl chitosan/calcium carbonate-chitosan(CCC) NPs and monomethoxy poly(ethylene glycol)-PLGA (mPP)NPs can rendezvous and dock primarily by hydrogen bonding, and electrostaticforces may be involved. Moreover, CCC@mPP NPs crossed the round windowmembrane (RWM) and entered the inner ear through endocytosis and paracellularpathway. The docking state was basically maintained during this process,which created favorable conditions for multidrug delivery. This nanosystemwas highly sensitive to pH and reactive oxygen species (ROS) changes,as evidenced by the restricted release of payload at alkaline condition(pH 7.4) without ROS, while significantly promoting the release inacidic condition (pH 5.0 and 6.0) with ROS. TSIIA/PNS/AB-loaded CCC@mPPNPs almost completely preserved the hair cells and remained the hearingthreshold shift within normal limits in aminoglycoside- or CDDP-treatedguinea pigs. Further experiments demonstrated that the protectivemechanisms of TSIIA/PNS/AB-loaded CCC@mPP NPs involved direct andindirect scavenging of excessive ROS, and reduced release of pro-inflammatorycytokines. Both in vitro and in vivo experiments showed the high biocompatibility of the composite NPs,even after long-term administration. Collectively, this work suggeststhat composite NPs is an ideal multi-drug-delivery vehicle and opennew avenues for inner ear disease therapies.