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Phosphodiesterase type V inhibitors (PDE5i) have been regarded as an alternative candidate drug for avoiding penile neuropathy. However, the therapeutic efficacy is severely limited due to poor accumulation under systemic medication and endogenous nitric oxide (NO) deficiency in cavernosum. Herein, an innovative liposomal microbubble (MB) loaded with both Sildenafil (one of PDE5i) and NO was designed. Ultrasound\u2010targeted MB destruction (UTMD)\u2010mediated efficient release and integration erectogenic agents into corpus cavernosum with high biosafety. On a bilateral CNI rat model, the multifunctional MB\u2010cooperated UTMD improved microvascular perfusion in penis, simultaneously, alleviated hypoxia and oxidative stress, indicating successful activation of NO\u2013cyclic guanosine monophosphate pathway. Also, evaluation of the endothelial\/muscular composition, intracavernosal pressure, and neural integrity in the penis proved that coordinated intervention reversed the abnormal structural remodeling and promoted the recovery of functional erection. Our work demonstrates that MB loading Sildenafil and NO combined with UTMD hold great promise to \u201cawaken\u201d the efficacy of PDE5i in neurogenic ED, which provided a superior option for ensuring penile rehabilitation.<\/jats:p>","DOI":"10.1002\/btm2.10568","type":"journal-article","created":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T01:15:45Z","timestamp":1688346945000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Ultrasound\u2010targeted microbubble destruction mediates <scp>PDE5i<\/scp>\/<scp>NO<\/scp> integration for cavernosum remodeling and penile rehabilitation"],"prefix":"10.1002","volume":"8","author":[{"given":"Wende","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Surgery The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Qiu","sequence":"additional","affiliation":[{"name":"Department of Medical Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"},{"name":"Department of Ultrasound The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiancheng","family":"Zhai","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengwu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Radiology Mayo Clinic College of Medicine and Science  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingke","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiology Mayo Clinic College of Medicine and Science  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Radiology Mayo Clinic College of Medicine and Science  Rochester Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Medical Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Medical Ultrasound, Laboratory of Novel Optoacoustic (Ultrasonic) Imaging The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1809-6544","authenticated-orcid":false,"given":"Hongbo","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery The Third Affiliated Hospital of Sun Yat\u2010sen University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,2]]},"reference":[{"issue":"4","key":"e_1_2_10_2_1","first-page":"181","article-title":"Consensus development conference statement. 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