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However, the rational engineering design of microcapsule-based composite adjuvant systems to elicit robust immune responses remains a significant challenge. Methods: This study developed polylactic acid (PLA) microcapsules with spatiotemporally coupled delivery and immunopotentiator properties. The resulting formulations were assessed for humoral and cellular immune responses in mice. Results: We prepared uniform-sized microcapsules (MC) and formulated them with monophosphoryl lipid A (MPLA) as a composite component (MPLA@MC), with hydrodynamic diameters of 4.58 \u03bcm and 4.12 \u03bcm, respectively. Such composite adjuvants, when loaded with ovalbumin (OVA) to form OVA@MC and OVA&amp;MPLA@MC, promoted cellular uptake and activation, exhibiting preferred lysosomal escape advantages. For in vivo experiments, microcapsule-based vaccines elevated serum levels of IgG antibody, and OVA&amp;MPLA@MC induced Th1-biased antibody responses. Specifically, OVA&amp;MPLA@MC also elicited strong cellular immune responses compared to other vaccines, as evidenced by increased secretion of Interferon-\u03b3 (IFN-\u03b3) in mouse splenocytes and Granzyme B (Gzmb) in T cells. Mechanistically, muscle tissues at the injection site showed that microcapsule-based vaccines enhanced the recruitment for phagocytosis. Meanwhile, bulk RNA sequencing (RNA-seq) confirmed extensive activation of immune responses and related signaling pathways. Conclusions: This rationally designed composite strategy for spatiotemporally coupled delivery serves as a potent platform for orchestrating synergistic immune responses, opening up new avenues for the development of effective therapeutic and anti-infectious vaccines.<\/jats:p>","DOI":"10.3390\/pharmaceutics18040456","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T08:56:07Z","timestamp":1775724967000},"page":"456","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Engineered Polylactic Acid (PLA) Microcapsules for Spatiotemporally Coupled Delivery and Synergistically Enhanced Dual Immunity"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7192-6302","authenticated-orcid":false,"given":"Shaoyu","family":"Guan","sequence":"first","affiliation":[{"name":"Pharmaceutical Sciences Research Division, Department of Pharmacy, Medical Supplies Centre of PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyi","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialu","family":"Li","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Research Division, Department of Pharmacy, Medical Supplies Centre of PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisha","family":"Wang","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Research Division, Department of Pharmacy, Medical Supplies Centre of PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2621-8326","authenticated-orcid":false,"given":"Hua","family":"Yue","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biopharmaceutical Preparation and Delivery, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fenghua","family":"Xu","sequence":"additional","affiliation":[{"name":"Pharmaceutical Sciences Research Division, Department of Pharmacy, Medical Supplies Centre of PLA General Hospital, Medical School of Chinese PLA, Beijing 100853, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.1016\/j.cell.2019.04.012","article-title":"Slow Delivery Immunization Enhances HIV Neutralizing Antibody and Germinal Center Responses via Modulation of Immunodominance","volume":"177","author":"Cirelli","year":"2019","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Li, Y., Tian, S., Ai, Y., Hu, Z., Ma, C., Fu, M., Xu, Z., Li, Y., Liu, S., and Zou, Y. 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