{"doi":"10.1021/acsami.5c04736","title":"Tuning Hyaluronic Acid Microstructures by Engineered Amphiphilicity: From Dynamically Cross-Linked Gels to Multilayered Nanoparticles","abstract":"Amphiphilic biopolymers are of interest for regenerative medicine applications due to their potential to interact with both hydrophobic and hydrophilic bioactive molecules and self-assemble into well-defined microstructures. We show that the amphiphilicity and microstructures of hydrophilic hyaluronic acid (HA) can be explicitly tuned by the stoichiometric integration of cholesterol to azide-functionalized HA via strain-promoted azide–alkyne cycloaddition (SPAAC). At low cholesterol contents, the hydrophobic interactions among the cholesterol units dynamically cross-link cholesteryl HA into physical gels showing enhanced and recoverable viscosities. By SPAAC cross-linking of remaining azides, the interdependence of physical and chemical cross-linking of cholesteryl HA is demonstrated. At higher cholesterol contents, cholesteryl HA self-assembles into multilamellar nanoparticles (NPs) composed of a core of alternately packed cholesterol-rich and HA-rich layers and a hydrated HA-rich outer layer. The amphiphilic NPs not only readily encapsulate hydrophobic compounds but also protect hydrophilic vitamin C from fast degradation in aqueous media. Rapid internalization of cholesteryl HA NPs by rat bone marrow-derived stromal cells and robust in vitro osteogenesis induced by NPs preloaded with dexamethasone and vitamin C were demonstrated. From viscoelastic physical gels, dual-cross-linked gels, to multilamellar NPs, cholesteryl HA with tailored amphiphilicity can be leveraged as versatile macromolecular building blocks for a wide range of regenerative medicine applications.","journal":"ACS Applied Materials & Interfaces","year":2025,"id":539505,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9492,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":503170,"name":"Aidan P. McAnena","orcid":"0000-0002-6466-6106","position":1,"is_corresponding":false},{"id":1426578,"name":"Joshua Kim","orcid":"0000-0003-2903-1073","position":2,"is_corresponding":false},{"id":1093426,"name":"Jie Song","orcid":"0000-0001-7554-5564","position":3,"is_corresponding":false},{"id":1093423,"name":"Shing‐Yun Chang","orcid":"0000-0003-2669-7574","position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:52:30.048313Z","pmid":"40415248","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}