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Here, the development of a non\u2010toxic, non\u2010hemolytic, and antifouling 3D star\u2010shaped auto\u2010degradable zwitterionic nano\u2010delivery system is reported to achieve maximum therapeutic efficacy in pancreatic tumor\u2010bearing mice xenografts. Nano\u2010compartmentalized star\u2010zwitterionic system is built by layer\u2010by\u2010layer block copolymer strategy by carefully choosing lysosomal enzyme\u2010biodegradable neutral hydrophobic polycaprolactone (PCL), anionic carboxylic PCL (CPCL), and cationic self\u2010immolative poly(amino\u2010ester, PAE). In vitro live\u2010cell studies established the synergistic on\u2010demand auto\u2010degradation of the star\u2010zwitterion in endo\u2010lysosomal compartments and release of the loaded cargoes at the intracellular level. Deep\u2010tissue penetrable NIR biomarker\u2010assisted in vivo live\u2010animal bioimaging in tumor\u2010bearing mice confirmed the stability and prolonged blood circulation of star\u2010zwitterion for more than 72\u00a0h and its ability to penetrate and be retained via passive targeting in the tumor site. The star\u2010zwitterion is self\u2010assembled into \u224825\u00a0nm tiny nanoparticle, exhibited electroneutrality under physiological pH, high drug loading content for clinical drug doxorubicin (DOX), alongside excellent nano\u2010formulation serum stability. Efficacy studies validated that the DOX delivery from the star\u2010zwitterionic platform is remarkable in suppressing pancreatic tumor volume in mice xenografts, suggesting their long\u2010term usefulness in cancer treatment.<\/jats:p>","DOI":"10.1002\/smll.202509518","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T13:28:36Z","timestamp":1761658116000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Autodegradable Polyzwitterionic Nanoplatform to Target and Suppress Solid Tumor in Mice Xenografts"],"prefix":"10.1002","volume":"21","author":[{"given":"Shahidkhan","family":"Pathan","sequence":"first","affiliation":[{"name":"Department of Chemistry Indian Institute of Science Education and Research Pune (IISER Pune)  Dr. Homi Bhabha Road Pune Maharashtra 411008 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