{"doi":"10.1101/2025.10.01.679807","title":"Nanochirality-programmed Type-I photosensitizer enables deep-tumor photodynamic therapy by reducing extracellular-matrix adhesion","abstract":"Abstract Tumor hypoxia and poor penetration of therapeutics across tumor-microenvironment barriers remain major obstacles to effective cancer therapy, including photodynamic therapy (PDT). Here we introduce a nanochirality-programmed assembly ( L -Chi-GAIN) in which nanochirality drives site-selective assembly that activates oxygen-independent Type-I reactive oxygen species (ROS) generation and reduces hyaluronan-mediated matrix adhesion, thereby permitting deep intratumoral therapy. Glycosylation imparts structural chirality to graphene quantum dots (GQDs), directing site-selective assembly of indocyanine green (ICG) that turns on photoinduced electron transfer (PET), producing a 64-fold increase in ROS relative to free ICG. Nanochirality also modulates assembly–extracellular matrix (ECM) interactions. L -GQDs show a less favorable hyaluronan binding free energy (ΔG bind ), thus accelerating interstitial transport and resulting in ∼21-fold deeper tumor penetration by L -Chi-GAIN than conventional nanocarriers. Under near-infrared irradiation, L -Chi-GAIN elicits strong oxidative stress and triggers Gasdermin-D (GSDMD)-dependent pyroptosis, leading to significant suppression of tumor growth. This work offers a nanochirality-guided design strategy for PDT in deep tumors by coupling site-selective assembly with stereoselective navigation of the ECM.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":556806,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9499,"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":278293,"name":"Gaeun Kim","orcid":"0009-0008-1502-1847","position":1,"is_corresponding":false},{"id":991682,"name":"Runyao Zhu","orcid":"0009-0005-5109-0020","position":2,"is_corresponding":false},{"id":1179393,"name":"Hyunsu Jeon","orcid":"0000-0001-8546-301X","position":3,"is_corresponding":false},{"id":436534,"name":"Yichun Wang","orcid":"0000-0002-4353-6660","position":4,"is_corresponding":false},{"id":1340599,"name":"Yichen Liu","orcid":"0000-0002-1547-7640","position":0,"is_corresponding":true}],"reference_count":49,"raw_metadata":null,"created_at":"2026-07-19T02:55:13.130091Z","pmid":"41256657","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":[]}