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Current treatments, largely centered on neurohormonal blockades, attenuate maladaptive pathways but do not restore endogenous cardioprotective systems. Among these, the natriuretic peptide (NP) network plays a central role in counteracting fibrosis, hypertrophy, sodium retention, and microvascular dysfunction. In advanced HF, impaired prohormone processing, corin dysfunction, and abnormal glycosylation lead to the predominance of biologically less-active NP forms despite elevated circulating levels, resulting in \u201cfunctional NP deficiency\u201d and insufficient NP\u2013cGMP signaling. From a mechanistic perspective, NP biology can be organized into two complementary axes. The cGMP-dependent axis comprises ANP and BNP signaling via NPR-A and CNP via NPR-B, mediating natriuretic, vasodilatory, and antifibrotic effects. The cGMP-independent axis includes NPR C-mediated signaling and the actions of the ANP mid-sequence fragment proANP31-67, which exerts antifibrotic and cardioprotective effects through a cyclooxygenase\u22122\/prostaglandin E\u2082\/EP4 pathway with minimal systemic hypotension. Nanomedicine offers a strategy to restore these complementary pathways with improved spatiotemporal precision. Lipid and polymeric nanoparticles, biomimetic carriers, and extracellular vesicles can protect NP-derived cargo, prolong bioavailability, and enhance functional cardiac targeting while limiting off-target exposure,\u00a0although current evidence is largely preclinical. In this review, we examine NP biology in post-ischemic remodeling, the concept of functional NP deficiency, and emerging nano-enabled delivery approaches as potential add-on interventions to contemporary HF therapy. We propose dual-axis \u201cnano-hormonal\u201d strategies integrating cGMP-dependent and cGMP-independent signaling as a testable paradigm for targeted modulation of post-MI remodeling.<\/jats:p>","DOI":"10.1007\/s11739-026-04500-0","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T17:26:06Z","timestamp":1787937966000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Nano-enabled natriuretic peptide therapy in post-myocardial infarction heart failure: from functional NP deficiency to dual-axis (cGMP-dependent and -independent) cardioprotection"],"prefix":"10.1007","author":[{"given":"Giulia","family":"Cevoli","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Isaia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reza","family":"Parvan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horng H.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Malatino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr.","given":"John C.","family":"Burnett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5476-8523","authenticated-orcid":false,"given":"Alessandro","family":"Cataliotti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"key":"4500_CR1","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1002\/ehf2.13144","volume":"8","author":"D Jenca","year":"2021","unstructured":"Jenca D, Melenovsky V, Stehlik J, Stanek V, Kettner J, Kautzner J, Adamkova V, Wohlfahrt P (2021) Heart failure after myocardial infarction: incidence and predictors. 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Alessandro Cataliotti has received research funding from the Norwegian Health Association, served as a scientific advisor for Madeleine Pharmaceuticals, and is a co-inventor on patents related to natriuretic peptide-based diagnostics and therapies for cardiovascular and renal diseases. John C. Burnett Jr has received NIH funding, is an inventor or co-inventor on multiple patents related to natriuretic peptide-based diagnostics and therapies, and has contributed to the founding of biotechnology companies developing natriuretic peptide-based therapeutics. Horng H. Chen is a co-inventor on patents related to natriuretic peptide-based therapies and is co-founder of Zumbro Discovery Inc. Ivan Isaia, Reza Parvan, and Lorenzo Malatino declare that they have no conflicts of interest relevant to this work.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"As this manuscript is a review article, ethical approval and patient consent were not required.","order":2,"name":"Ethics","label":"Ethical statements","group":{"name":"EthicsHeading","label":"Declarations"}}]}}