Yinan Zhao

Solid tumors pose a spatial “delivery-at-depth” bottleneck: therapeutics that reach tumors often remain sequestered near vessels and fail to distribute uniformly into tumor cores. This limitation arises from heterogeneous perfusion, elevated interstitial fluid pressure, and dense extracellular matrix, which together restrict convection–diffusion balance and amplify binding-site barriers. We organize transformable and bioinspired nanomedicines using a barrier-centric lens and summarize five strategy families to deepen and homogenize intratumoral transport: (i) stimuli-responsive size/charge switching, (ii) microenvironment remodeling to restore perfusion and decompress stroma, (iii) ligand-guided transcytosis and CendR pathway engagement, (iv) cell-based and biomimetic vectors leveraging homing and immune evasion, and (v) multistage designs that sequence priming, switching, and payload activation. We compare representative systems by trigger specificity, activation timing, affinity tuning, and corona susceptibility, and highlight recurring failure modes including stimulus heterogeneity, premature/off-target activation, and escalating chemistry–manufacturing–controls burdens with added components. We conclude with translational priorities: couple barrier priming with a single well-characterized switching event, favor moderated or activatable affinity to avoid perivascular trapping, and validate spatial gains using standardized intratumoral distribution metrics linked to therapeutic endpoints. Graphical Abstract

The antiglycation mechanisms of three structurally different salvianolic acids (Sals) including salvianolic acid A (Sal-A), salvianolic acid B (Sal-B) and salvianolic acid C (Sal-C) were investigated using the bovine serum albumin (BSA)-fructose model. The results showed that the three compounds could inhibit the formation of glycation products, maintain protein structural stability, mitigate the development of amyloid fibrils and scavenge radicals. Notably, Sal-A possessed the highest anti-glycated activity compared with Sal-B and Sal-C. This may be related to the fact that Sal-A contained the most molecules of caffeic acid (Sal-A, Sal-B, and Sal-C possessing two, one, and zero caffeic acid units, respectively), and caffeic acid played a leading role in the antiglycation properties relative to Danshensu. Moreover, these compounds quenched the intrinsic fluorescence intensity of BSA in a static mode, with the binding constants in the order of Sal-A > Sal-B > Sal-C. Obviously, Sal-A possessed the strongest binding affinity among these compounds, which may be one of the reasons why it exhibited the optimal antiglycation capability. Furthermore, molecular docking demonstrated that the three Sals exerted protective effects on BSA by preventing glycation modification of lysine and arginine residues. These findings would provide valuable insights into the potential application of Sals for alleviating non-enzymatic glycation of protein.

Although many carriers for the delivery of chemotherapeutic drugs have been investigated, the disadvantages of passive targeting and uncontrolled drug release limit their utility. Herein, hyaluronic acid (HA) was hydrophobically modified to serve as a carrier for binding to cluster determinant 44 (CD44) overexpressed on tumor cell surfaces. Specifically, after deacetylation, HA was grafted to dodecylamine or tetradecylamine to afford amphiphilic zwitterionic polymer micelles, designated dHAD and dHAT, respectively, for the delivery of paclitaxel (PTX). The micelles were negatively charged at pH 7.4 and positively charged at pH 5.6, and this pH sensitivity facilitated PTX release under acidic conditions. The cell uptake efficiencies of the dHAD-PTX and dHAT-PTX micelles by MCF-7 cells after 4 h of incubation were 96.9% and 95.4%, respectively, and their affinities for CD44 were twice that of HA. Furthermore, the micelles markedly inhibited tumor growth both in vitro and in vivo, with IC₅₀ values of 1.943 μg/mL for dHAD-PTX and 1.874 μg/mL for dHAT-PTX for MCF-7 cells; the tumor inhibition rate of dHAD-PTX (92.96%) was higher than that of dHAT-PTX (78.65%). Importantly, dHAD and dHAT micelles showed negligible systemic toxicity. Our findings suggest that these micelles are promising delivery vehicles for antitumor drugs.