PMID- 36280028 OWN - NLM STAT- MEDLINE DCOM- 20221216 LR - 20221221 IS - 1878-7568 (Electronic) IS - 1742-7061 (Linking) VI - 154 DP - 2022 Dec TI - Surface-anchored tumor microenvironment-responsive protein nanogel-platelet system for cytosolic delivery of therapeutic protein in the post-surgical cancer treatment. PG - 412-423 LID - S1742-7061(22)00687-0 [pii] LID - 10.1016/j.actbio.2022.10.031 [doi] AB - Nanoparticle-anchored platelet systems hold great potential to act as drug carriers in post-surgical cancer treatment due to their intrinsic ability to target the bleeding sites. However, rational design is still needed to further improve its cargo release profiles to meet the cytosolic delivery of therapeutic proteins with intracellular targets. Herein, we developed a tumor microenvironment (TME)-responsive backpack-conjugated platelet system to enhance intracellular protein delivery, thereby significantly inhibiting tumor recurrence after surgery. Specifically, protein nanogels encapsulating GALA and Granzyme B (GrB) are conjugated on the platelet surface via an acid-sensitive benzoic-imine linker through a biorthogonal reaction (GALA-GNGs-P). Taking advantage of wound-tropism of platelets, GALA-GNGs-P could actively accumulate at the surgical trauma and release nanogels in response to acidic TME for promoting deep penetration. Following cellular uptake, the pore-forming peptide GALA helps nanogels escape from lysosome. Subsequently, high glutathione (GSH) concentration in tumor cytoplasm facilitates GrB release from NGs, leading to intense cell apoptosis. GALA-GNGs-P shows remarkable tumor-targeting capability, high cellular uptake, and outstanding lysosomal escaping ability, which can significantly inhibit tumor recurrence in mice models with incomplete tumor resection. Our findings indicate that platelets bioengineered with TME-responsive protein nanogels provide an option to intracellularly deliver therapeutic proteins for the post-surgical treatment of cancer. STATEMENT OF SIGNIFICANCE: Platelet-based drug delivery systems (DDSs) have gained considerable achievements in post-surgical cancer treatment. However, there is no research exploring their potential in realizing the controllable release of cargoes in the acidic tumor microenvironment (TME). Herein, we developed a TME-responsive bioengineered platelet delivery platform (GALA-GNGs-P) for achieving controllable and effective protein intracellular delivery to overcome post-surgical tumor recurrence. Our surface-anchored nanogel-platelet system has the following advantages: (i) improving the loading efficiency of therapeutic proteins, (ii) affecting no physiological function of platelets, (iii) realizing on-demand cargo release in the acidic TME, and (iv) helping proteins escape from endosomal entrapment. Our findings further explored the prospect of cellular backpack system and realized the controllable release of cargoes in the acidic TME. CI - Copyright (c) 2022. Published by Elsevier Ltd. FAU - Fan, Xiaoyuan AU - Fan X AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Wang, Kaiyuan AU - Wang K AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Lu, Qi AU - Lu Q AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Lu, Yutong AU - Lu Y AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Liu, Fengxiang AU - Liu F AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Li, Lu AU - Li L AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Li, Songhao AU - Li S AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Ye, Hao AU - Ye H AD - Multi-Scale Robotics Lab (MSRL), Institute of Robotics & Intelligent Systems (IRIS), ETH Zurich, 8092 Zurich, Switzerland. FAU - Zhao, Jian AU - Zhao J AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Cao, Liping AU - Cao L AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Zhang, Haotian AU - Zhang H AD - School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang Liaoning 110016, China. FAU - He, Zhonggui AU - He Z AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. FAU - Sun, Jin AU - Sun J AD - Department of Pharmaceutics, Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: sunjin@syphu.edu.cn. LA - eng PT - Journal Article DEP - 20221021 PL - England TA - Acta Biomater JT - Acta biomaterialia JID - 101233144 RN - 0 (Membrane Proteins) RN - 0 (polyethylene glycol polyethyleneimine nanogel) RN - 0 (Nanogels) SB - IM MH - Mice MH - Animals MH - *Tumor Microenvironment MH - Membrane Proteins MH - Neoplasm Recurrence, Local/drug therapy MH - Nanogels MH - Drug Delivery Systems MH - *Neoplasms/drug therapy OTO - NOTNLM OT - Nanoparticle-anchored platelets OT - Post-surgical therapy OT - TME-responsive cellular backpacks OT - Tumor recurrence inhibition OT - Tumor-targeting capability COIS- Declaration of Competing Interest The authors report no conflicts of interest. EDAT- 2022/10/25 06:00 MHDA- 2022/12/15 06:00 CRDT- 2022/10/24 19:25 PHST- 2022/08/25 00:00 [received] PHST- 2022/10/10 00:00 [revised] PHST- 2022/10/14 00:00 [accepted] PHST- 2022/10/25 06:00 [pubmed] PHST- 2022/12/15 06:00 [medline] PHST- 2022/10/24 19:25 [entrez] AID - S1742-7061(22)00687-0 [pii] AID - 10.1016/j.actbio.2022.10.031 [doi] PST - ppublish SO - Acta Biomater. 2022 Dec;154:412-423. doi: 10.1016/j.actbio.2022.10.031. Epub 2022 Oct 21.