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Herein, a dual \u201cunlocking\u201d strategy to overcome these obstacles is proposed by combining engineered hybrid nanoparticles (named ZnPc@FOM\u2010Pt) with dexamethasone (DXM). It is verified that pretreatment of tumors with DXM can increase intratumorally micro\u2010vessel density (delivery \u201cunlocking\u201d) to enhance the tumor delivery efficiency of ZnPc@FOM\u2010Pt and decrease HIF\u20101<jats:italic>\u03b1<\/jats:italic> expression. Correspondingly, more Pt can catalyze tumor\u2010overexpressed H<jats:sub>2<\/jats:sub>O<jats:sub>2<\/jats:sub> to produce oxygen to further cause hypoxia \u201cunlocking,\u201d ultimately achieving boosted ZnPc\u2010based photodynamic therapy in vivo (tumor inhibition rate: 99.1%). Moreover, the immunosuppressive tumor microenvironment is efficiently reversed and the therapeutic effect of anti\u2010PD\u2010L1\u2010based immunotherapy is promoted by this newly designed nanomedicine. This dual \u201cunlocking\u201d strategy provides an innovative paradigm on simultaneously enhancing nanomedicine delivery efficacy and hypoxia relief for tumor therapy.<\/jats:p>","DOI":"10.1002\/adhm.202202467","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T03:44:24Z","timestamp":1668483864000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Dual \u201cUnlocking\u201d Strategy to Overcome Inefficient Nanomedicine Delivery and Tumor Hypoxia for Enhanced Photodynamic\u2010Immunotherapy"],"prefix":"10.1002","volume":"12","author":[{"given":"Xianglong","family":"Li","sequence":"first","affiliation":[{"name":"Lab of Low\u2010Dimensional Materials Chemistry Key Laboratory for Ultrafine Materials of Ministry of Education Frontier Science Center of the Materials Biology and Dynamic Chemistry Shanghai Engineering Research Center of Hierarchical Nanomaterials School of Materials Science and Engineering East China University of Science and Technology  Shanghai 200237 P. 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