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Main Author:	Dilpreet Singh
Format:	Artículo Open Access
Published:	Wiley 2026
Subjects:	Journal of Peptide Science
Online Access:	https://onlinelibrary.wiley.com/doi/10.1002/psc.70105
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Structure‐Guided Engineering of Histidine‐Rich pH‐Switchable Endosomolytic Peptides for Spleen‐Selective siRNA Delivery to Inflammatory Macrophages Dilpreet Singh Journal of Peptide Science ABSTRACT Extrahepatic delivery of small interfering RNA (siRNA) remains a major translational challenge because most nanocarriers preferentially accumulate in the liver, while endosomal sequestration limits productive cytosolic release. Inflammatory macrophages in the spleen are attractive therapeutic targets in systemic inflammation, yet spleen‐selective delivery systems with efficient endosomal escape remain underdeveloped. Here, a structure‐guided peptide engineering workflow was used to generate histidine‐rich, pH‐switchable endosomolytic peptides for spleen‐selective siRNA delivery. Sequence design integrated pH‐dependent charge transition modeling, amphipathic helix prediction, membrane interaction scoring, and safety filtering. Six candidate peptides were synthesized and evaluated for pH‐responsive structure, membrane disruption, hemocompatibility, siRNA complexation, serum stability, macrophage uptake, endosomal escape, biodistribution, and anti‐inflammatory efficacy. The lead peptide, HSEP‐6, showed a predicted net charge increase from +3.1 at pH 7.4 to +7.4 at pH 5.5, helix content increasing from 17% to 56%, and acidic calcein release increasing from 9% to 62%. In inflammatory macrophages and LPS‐challenged mice, HSEP‐6 enabled efficient siRNA delivery, spleen‐selective accumulation, marked Irf5 silencing, reduced TNF‐α and IL‐6, and no measurable systemic toxicity, supporting histidine‐rich pH‐switchable peptides as a rational platform for extrahepatic RNA delivery. 10.1002/psc.70105 http://onlinelibrary.wiley.com/termsAndConditions#vor

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// Anecdotal testing Today and Yesterday seems to indicate destroy() // is called by the garbage collector and everything is good. // Something to keep in mind though. return 0; } /** * Write function that is called when session data is to be saved. * * @param string $sessId The current session ID * @param string $data The session data to write * * @return bool */ public function write($sessId, $data): bool { if ($this->writesDisabled) { return true; } return $this->saveSession($sessId, $data); } /** * A function that is called internally when session data is to be saved. * * @param string $sessId The current session ID * @param string $data The session data to write * * @return bool */ abstract protected function saveSession($sessId, $data): bool; }

* * @return void */ public function writeClose() { // The assumption is that we're using PHP's ext/session. // session_write_close() will actually overwrite $_SESSION with an // empty array on completion -- which leads to a mismatch between what // is in the storage object and $_SESSION. To get around this, we // temporarily reset $_SESSION to an array, and then re-link it to // the storage object. // // Additionally, while you _can_ write to $_SESSION following a // session_write_close() operation, no changes made to it will be // flushed to the session handler. As such, we now mark the storage // object isImmutable. $storage = $this->getStorage(); if (! $storage->isImmutable()) { $_SESSION = $storage->toArray(true); session_write_close(); $storage->fromArray($_SESSION); $storage->markImmutable(); } } /** * Attempt to set the session name * * If the session has already been started, or if the name provided fails * validation, an exception will be raised. * * @param string $name * @return SessionManager * @throws Exception\InvalidArgumentException */ public function setName($name) { if ($this->sessionExists()) { throw new Exception\InvalidArgumentException( 'Cannot set session name after a session has already started'

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