Senti Biosciences Holdings Inc. American Stock Prospectus (2026-05-01 Edition)

Up to $17,500,000 Common Stock This Prospectus Supplement No.1 (this “Supplement No.1”) to the Prospectus Supplement supplements and amends the Prospectus Supplement datedMarch31, 2025 (the “ATM Prospectus Supplement”) and the base prospectus dated March31, 2025 (the “Base Prospectus”) included in theRegistration Statement on Form S-3 (File No.333-285985), each filed by Senti Biosciences, Inc. (the “Predecessor Registrant”) with the Securities andExchange Commission (the “Commission”) on March20, 2025, which registration statement was declared effective with the Commission on March31,2025. The ATM Prospectus Supplement related to the sale of shares of the Predecessor Registrant’s common stock, par value $0.0001 per share(“Predecessor Registrant Common Stock”) in accordance with the terms of a sales agreement (the “sales agreement”) with Leerink Partners LLC(“Leerink Partners”), as the Predecessor Registrant’s sales agent (the “sales agent”). In accordance with the terms of the sales agreement, thePredecessor Registrant may offer and sell shares of the Predecessor Registrant Common Stock having an aggregate offering price of up to $17,500,000from time to time through Leerink Partners, acting as the sales agent. As of the date of this Supplement No.1, approximately $6.0million remainedunsold pursuant to the ATM Prospectus Supplement and the sales agreement. On April24, 2026, Senti Biosciences Holdings, Inc., a Delaware corporation (the “Company”) filed Post-Effective Amendment No.1 to RegistrationStatement on Form S-3 (as so amended and supplemented, the “Registration Statement”). The Company became the successor to the PredecessorRegistrant on April24, 2026 for purposes of paragraph (d)of Rule 414 under the Securities Act of 1933, as amended, as a result of the adoption by thePredecessor Registrant of a holding company form of organizational structure (the “Reorganization”) implemented in accordance with Section251(g) ofthe Delaware General Corporation Law by the merger (the “Merger”) of the Predecessor Registrant with Senti Biosciences Merger Sub, Inc., a Delawarecorporation (the “Merger Sub”) and a direct, wholly owned subsidiary of Senti Holdings, Inc., a Delaware corporation (“Senti Holdings”) and a direct, Following the consummation of the Reorganization, the Company’s common stock continues to trade on the Nasdaq Capital Market (the “Nasdaq”)under the ticker symbol “SNTI” with a new CUSIP number (816944 102). Immediately following the consummation of the Reorganization, on a As a result of the Merger, the Company assumed the rights and obligations of the Predecessor Registrant under the sales agreement and the ATMProspectus Supplement and Base Prospectus, as supplemented by this Supplement No.1, relate to the offer and sale by the Company, as successor This Supplement No.1 is not complete without, and may not be delivered or used except in connection with, the ATM Prospectus Supplement and theBase Prospectus. INVESTING IN THE COMPANY’S COMMON STOCK INVOLVES A HIGH DEGREE OF RISK. BEFOREMAKING AN INVESTMENT DECISION, YOU SHOULD CAREFULLY CONSIDER ALL OF THE INFORMATIONSET FORTH IN THIS PROSPECTUS SUPPLEMENT, THE ATM PROSPECTUS SUPPLEMENT AND THE Neither the Securities and Exchange Commission nor any state securities commission has approved or disapproved of the securities to be issuedunder this prospectus supplement or determined if this prospectus supplement is truthful or complete. Any representation to the contrary is acriminal offense. Leerink Partners The date of this Supplement No.1 is May1, 2026.