Effects Of A Nanoparticle’s Elasticity On Its Physiological Fate And The Uderlying Mechanisms

Currently,nanoparticles are widely used in various biomedical applications,such as vaccines,diagnostic imaging,drug delivery,and therapy.In order to improve the performance of nanoparticles in vivo,researchers have focused on adjusting the physical and chemical synthesis parameters of nanoparticles(including size,shape,and surface chemistry)and observed the effects of these parameters on the physiological fate of particles,such as blood circulation and in vivo distribution.These observations can be used to guide the rational design of nanoparticles.The elasticity of nanoparticles is a physical and chemical parameter that has not been fully studied by researchers in the past,but has recently been found to play a crucial role in the physiological performance of nanoparticles.Although similar to other physical and chemical parameters of nanoparticles(such as size,shape,and surface chemistry),there is increasing evidence that nanoparticle elasticity plays a crucial role in cellular uptake efficiency,the ways of cellular internalization,in vivo circulation lifespan,and biological distribution,but there is still controversy and contradiction regarding how nanoparticle elasticity affects physiological fate,and the results are still unclear.Furthermore,the potential mechanisms by which nanoparticle elasticity plays a role are still unknown.After nanoparticles enter the biological system,proteins in the body fluids will quickly adsorb onto the particle surface due to the particle’s high surface energy,forming a protein corona on the surface of the nanoparticle.Studies have shown that the protein corona on the outer layer of the particle,rather than the physical and chemical synthesis parameters of the particle itself(such as size,shape,and surface chemistry),is the key factor that determines the particle’s identity and in vivo fate.Currently,in order to rationally use the protein corona,more work has been done to explore how particle size,shape,and surface chemistry affect the composition of the protein corona.However,no report has systematically studied the effect of nanoparticle elasticity on the protein corona,even though nanoparticle elasticity is crucial for the physiological fate of nanoparticles.Based on the above background,this study carefully designed nanoparticles that only vary in elasticity to investigate the exact effect of particle elasticity on physiological fate and to explore the underlying mechanisms.Firstly,we used core-shell nanoparticles with the same PEGylated lipid bilayer shell but different core elasticity(45 kPa-760 MPa)as a model,whose elasticity is continuous and adjustable,to separate the effect of nanoparticle elasticity from the effect of other physicochemical parameters,and to explore the mechanism by which nanoparticle elasticity regulates the physiological fate of nanoparticles.This overcame the problems in previous literature where particle design did not exclude interference from other parameters(such as different cross-linked hydrogel particles with different surface pore and functional group densities),the particle elasticity range was too small,or the span was too large.In the subsequent investigation of physiological fate,we found that when the particle elasticity was harder(>106 kPa),the uptake was higher than that of other particles(<106 kPa).However,when the particles were not that hard(<106 kPa),the efficiency of uptake was uncertain.The circulation lifespan of particles exhibited a clear but non-monotonic change with nanoparticle elasticity,which differs from the simple conclusion described in previous literature that "the softer the particle,the longer the circulation lifespan".Instead,the influence can be divided into three regions which were<15 kPa,15 kPa-75 kPa,and>75 kPa.In each region,the softer the particle,the longer the circulation lifespan,consistent with the previous generalization.However,the middle region has the shortest blood circulation time compared to other regions.Our conclusion validated the conclusions in the literature and provides a more global perspective on this basis.In order to further explore the potential mechanism of elasticity affecting the physiological fate of nanoparticles,we used two sets of core-shell nanoparticle models with the same PEGylated synthetic or non-PEGylated natural lipid bilayer shell but different core elasticities.We found that the elasticity of nanoparticles can change both the total protein amount and the adsorbed protein pattern in the protein corona.Among them,Apolipoprotein A-I(ApoAl)had the greatest amount on the surface of nanoparticles with intermediate elasticity.Further correlation analysis showed that ApoAl in the protein corona was the only protein significantly positively correlated with the blood circulation time of nanoparticles(correlation coefficient>0.6).We then demonstrated through a series of in vitro experiments that ApoAl played a role as a dysopsonin.We summarized the mechanism by which the elasticity of particles affects their in vivo circulation.The possible mechanism is that ApoAl preferentially adsorbs to nanoparticles with intermediate elasticity,then inhibiting their cellular uptake.In addition,softer nanoparticles are more easily escaped from organ filters,resulting in longer blood circulation time for particles with intermediate elasticity.This reveals the mechanism by which particle elasticity affects nanoparticle’s physiological fate and suggests that nanoparticle elasticity is an easy-to-regulate parameter for rational utilization of the protein corona,providing a certain design concept for future applications.