<?xml version="1.0" encoding="UTF-8"?>

<!--XBRL Document Created with Wdesk from Workiva-->
<!--Copyright 2022 Workiva-->
<!--r:b27b6e59-905d-4b25-864e-df08fef05dee,g:1c23ccd7-4504-4352-9e11-1c0cf2f9c200-->
<xs:schema xmlns:xs="http://www.w3.org/2001/XMLSchema" xmlns:link="http://www.xbrl.org/2003/linkbase" xmlns:naut="http://www.nautilus.bio/20220224" xmlns:xbrli="http://www.xbrl.org/2003/instance" xmlns:dtr-types="http://www.xbrl.org/dtr/type/2020-01-21" xmlns:xbrldt="http://xbrl.org/2005/xbrldt" attributeFormDefault="unqualified" elementFormDefault="qualified" targetNamespace="http://www.nautilus.bio/20220224">
  <xs:import namespace="http://fasb.org/srt/2021-01-31" schemaLocation="https://xbrl.fasb.org/srt/2021/elts/srt-2021-01-31.xsd"/>
  <xs:import namespace="http://fasb.org/us-gaap/2021-01-31" schemaLocation="https://xbrl.fasb.org/us-gaap/2021/elts/us-gaap-2021-01-31.xsd"/>
  <xs:import namespace="http://www.w3.org/1999/xlink" schemaLocation="http://www.xbrl.org/2003/xlink-2003-12-31.xsd"/>
  <xs:import namespace="http://www.xbrl.org/2003/instance" schemaLocation="http://www.xbrl.org/2003/xbrl-instance-2003-12-31.xsd"/>
  <xs:import namespace="http://www.xbrl.org/2003/linkbase" schemaLocation="http://www.xbrl.org/2003/xbrl-linkbase-2003-12-31.xsd"/>
  <xs:import namespace="http://www.xbrl.org/dtr/type/2020-01-21" schemaLocation="https://www.xbrl.org/dtr/type/2020-01-21/types.xsd"/>
  <xs:import namespace="http://xbrl.org/2005/xbrldt" schemaLocation="http://www.xbrl.org/2005/xbrldt-2005.xsd"/>
  <xs:import namespace="http://xbrl.sec.gov/dei/2021q4" schemaLocation="https://xbrl.sec.gov/dei/2021q4/dei-2021q4.xsd"/>
  <xs:annotation>
    <xs:appinfo>
      <link:linkbaseRef xmlns:xlink="http://www.w3.org/1999/xlink" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="naut-20220224_lab.xml" xlink:role="http://www.xbrl.org/2003/role/labelLinkbaseRef" xlink:type="simple"/>
      <link:linkbaseRef xmlns:xlink="http://www.w3.org/1999/xlink" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="naut-20220224_pre.xml" xlink:role="http://www.xbrl.org/2003/role/presentationLinkbaseRef" xlink:type="simple"/>
      <link:linkbaseRef xmlns:xlink="http://www.w3.org/1999/xlink" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="naut-20220224_cal.xml" xlink:role="http://www.xbrl.org/2003/role/calculationLinkbaseRef" xlink:type="simple"/>
      <link:linkbaseRef xmlns:xlink="http://www.w3.org/1999/xlink" xlink:arcrole="http://www.w3.org/1999/xlink/properties/linkbase" xlink:href="naut-20220224_def.xml" xlink:role="http://www.xbrl.org/2003/role/definitionLinkbaseRef" xlink:type="simple"/>
      <link:roleType id="Cover" roleURI="http://www.nautilus.bio/role/Cover">
        <link:definition>0001001 - Document - Cover</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ConsolidatedBalanceSheets" roleURI="http://www.nautilus.bio/role/ConsolidatedBalanceSheets">
        <link:definition>1001002 - Statement - Consolidated Balance Sheets</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ConsolidatedBalanceSheetsParenthetical" roleURI="http://www.nautilus.bio/role/ConsolidatedBalanceSheetsParenthetical">
        <link:definition>1402401 - Statement - Consolidated Balance Sheets (Parenthetical)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ConsolidatedStatementsofOperations" roleURI="http://www.nautilus.bio/role/ConsolidatedStatementsofOperations">
        <link:definition>1003003 - Statement - Consolidated Statements of Operations</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StatementsofComprehensiveLoss" roleURI="http://www.nautilus.bio/role/StatementsofComprehensiveLoss">
        <link:definition>1004004 - Statement - Statements of Comprehensive Loss</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StatementsofRedeemableConvertiblePreferredStockandStockholdersEquityDeficit" roleURI="http://www.nautilus.bio/role/StatementsofRedeemableConvertiblePreferredStockandStockholdersEquityDeficit">
        <link:definition>1005005 - Statement - Statements of Redeemable Convertible Preferred Stock and Stockholders&#8217; Equity (Deficit)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StatementsofCashFlows" roleURI="http://www.nautilus.bio/role/StatementsofCashFlows">
        <link:definition>1006006 - Statement - Statements of Cash Flows</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="DescriptionofBusinessandBasisofPresentation" roleURI="http://www.nautilus.bio/role/DescriptionofBusinessandBasisofPresentation">
        <link:definition>2101101 - Disclosure - Description of Business and Basis of Presentation</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="DescriptionofBusinessandBasisofPresentationNarrativeDetails" roleURI="http://www.nautilus.bio/role/DescriptionofBusinessandBasisofPresentationNarrativeDetails">
        <link:definition>2402402 - Disclosure - Description of Business and Basis of Presentation - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SignificantAccountingPolicies" roleURI="http://www.nautilus.bio/role/SignificantAccountingPolicies">
        <link:definition>2103102 - Disclosure - Significant Accounting Policies</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SignificantAccountingPoliciesPolicies" roleURI="http://www.nautilus.bio/role/SignificantAccountingPoliciesPolicies">
        <link:definition>2204201 - Disclosure - Significant Accounting Policies (Policies)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SignificantAccountingPoliciesTables" roleURI="http://www.nautilus.bio/role/SignificantAccountingPoliciesTables">
        <link:definition>2305301 - Disclosure - Significant Accounting Policies (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SignificantAccountingPoliciesDetails" roleURI="http://www.nautilus.bio/role/SignificantAccountingPoliciesDetails">
        <link:definition>2406403 - Disclosure - Significant Accounting Policies (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SignificantAccountingPoliciesUsefulLivesDetails" roleURI="http://www.nautilus.bio/role/SignificantAccountingPoliciesUsefulLivesDetails">
        <link:definition>2407404 - Disclosure - Significant Accounting Policies - Useful Lives (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ReverseRecapitalization" roleURI="http://www.nautilus.bio/role/ReverseRecapitalization">
        <link:definition>2108103 - Disclosure - Reverse Recapitalization</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ReverseRecapitalizationTables" roleURI="http://www.nautilus.bio/role/ReverseRecapitalizationTables">
        <link:definition>2309302 - Disclosure - Reverse Recapitalization (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ReverseRecapitalizationNarrativeDetails" roleURI="http://www.nautilus.bio/role/ReverseRecapitalizationNarrativeDetails">
        <link:definition>2410405 - Disclosure - Reverse Recapitalization - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="ReverseRecapitalizationSharesReconciliationDetails" roleURI="http://www.nautilus.bio/role/ReverseRecapitalizationSharesReconciliationDetails">
        <link:definition>2411406 - Disclosure - Reverse Recapitalization - Shares Reconciliation (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="FairValueMeasurements" roleURI="http://www.nautilus.bio/role/FairValueMeasurements">
        <link:definition>2112104 - Disclosure - Fair Value Measurements</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="FairValueMeasurementsTables" roleURI="http://www.nautilus.bio/role/FairValueMeasurementsTables">
        <link:definition>2313303 - Disclosure - Fair Value Measurements (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="FairValueMeasurementsAssetsCarriedatFairValueandMeasuredonaRecurringBasisDetails" roleURI="http://www.nautilus.bio/role/FairValueMeasurementsAssetsCarriedatFairValueandMeasuredonaRecurringBasisDetails">
        <link:definition>2414407 - Disclosure - Fair Value Measurements - Assets Carried at Fair Value and Measured on a Recurring Basis (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CompositionofCertainFinancialStatementLineItems" roleURI="http://www.nautilus.bio/role/CompositionofCertainFinancialStatementLineItems">
        <link:definition>2115105 - Disclosure - Composition of Certain Financial Statement Line Items</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CompositionofCertainFinancialStatementLineItemsTables" roleURI="http://www.nautilus.bio/role/CompositionofCertainFinancialStatementLineItemsTables">
        <link:definition>2316304 - Disclosure - Composition of Certain Financial Statement Line Items (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CompositionofCertainFinancialStatementLineItemsPropertyandEquipmentnetDetails" roleURI="http://www.nautilus.bio/role/CompositionofCertainFinancialStatementLineItemsPropertyandEquipmentnetDetails">
        <link:definition>2417408 - Disclosure - Composition of Certain Financial Statement Line Items - Property and Equipment, net (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CompositionofCertainFinancialStatementLineItemsOtherLongTermAssetsDetails" roleURI="http://www.nautilus.bio/role/CompositionofCertainFinancialStatementLineItemsOtherLongTermAssetsDetails">
        <link:definition>2418409 - Disclosure - Composition of Certain Financial Statement Line Items - Other Long Term Assets (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CompositionofCertainFinancialStatementLineItemsAccruedExpensesandOtherLiabilitiesDetails" roleURI="http://www.nautilus.bio/role/CompositionofCertainFinancialStatementLineItemsAccruedExpensesandOtherLiabilitiesDetails">
        <link:definition>2419410 - Disclosure - Composition of Certain Financial Statement Line Items - Accrued Expenses and Other Liabilities (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CompositionofCertainFinancialStatementLineItemsCashCashEquivalentsandRestrictedCashDetails" roleURI="http://www.nautilus.bio/role/CompositionofCertainFinancialStatementLineItemsCashCashEquivalentsandRestrictedCashDetails">
        <link:definition>2420411 - Disclosure - Composition of Certain Financial Statement Line Items - Cash, Cash Equivalents and Restricted Cash (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="RedeemableConvertiblePreferredStock" roleURI="http://www.nautilus.bio/role/RedeemableConvertiblePreferredStock">
        <link:definition>2121106 - Disclosure - Redeemable Convertible Preferred Stock</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="RedeemableConvertiblePreferredStockNarrativeDetails" roleURI="http://www.nautilus.bio/role/RedeemableConvertiblePreferredStockNarrativeDetails">
        <link:definition>2422412 - Disclosure - Redeemable Convertible Preferred Stock - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonStock" roleURI="http://www.nautilus.bio/role/CommonStock">
        <link:definition>2123107 - Disclosure - Common Stock</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonStockTables" roleURI="http://www.nautilus.bio/role/CommonStockTables">
        <link:definition>2324305 - Disclosure - Common Stock (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonStockNarrativeDetails" roleURI="http://www.nautilus.bio/role/CommonStockNarrativeDetails">
        <link:definition>2425413 - Disclosure - Common Stock - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonStockWarrantsDetails" roleURI="http://www.nautilus.bio/role/CommonStockWarrantsDetails">
        <link:definition>2426414 - Disclosure - Common Stock - Warrants (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommonStockCommonStockReservedforFutureIssuanceDetails" roleURI="http://www.nautilus.bio/role/CommonStockCommonStockReservedforFutureIssuanceDetails">
        <link:definition>2427415 - Disclosure - Common Stock - Common Stock Reserved for Future Issuance (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="IncomeTaxes" roleURI="http://www.nautilus.bio/role/IncomeTaxes">
        <link:definition>2128108 - Disclosure - Income Taxes</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="IncomeTaxesTables" roleURI="http://www.nautilus.bio/role/IncomeTaxesTables">
        <link:definition>2329306 - Disclosure - Income Taxes (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="IncomeTaxesNarrativeDetails" roleURI="http://www.nautilus.bio/role/IncomeTaxesNarrativeDetails">
        <link:definition>2430416 - Disclosure - Income Taxes - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="IncomeTaxesIncomeTaxReconciliationDetails" roleURI="http://www.nautilus.bio/role/IncomeTaxesIncomeTaxReconciliationDetails">
        <link:definition>2431417 - Disclosure - Income Taxes - Income Tax Reconciliation (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="IncomeTaxesDeferredTaxAssetsandLiabilitiesDetails" roleURI="http://www.nautilus.bio/role/IncomeTaxesDeferredTaxAssetsandLiabilitiesDetails">
        <link:definition>2432418 - Disclosure - Income Taxes - Deferred Tax Assets and Liabilities (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="IncomeTaxesUncertainTaxPositionsDetails" roleURI="http://www.nautilus.bio/role/IncomeTaxesUncertainTaxPositionsDetails">
        <link:definition>2433419 - Disclosure - Income Taxes - Uncertain Tax Positions (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockOptionPlanandStockbasedCompensation" roleURI="http://www.nautilus.bio/role/StockOptionPlanandStockbasedCompensation">
        <link:definition>2134109 - Disclosure - Stock Option Plan and Stock-based Compensation</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockOptionPlanandStockbasedCompensationTables" roleURI="http://www.nautilus.bio/role/StockOptionPlanandStockbasedCompensationTables">
        <link:definition>2335307 - Disclosure - Stock Option Plan and Stock-based Compensation (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockOptionPlanandStockbasedCompensationNarrativeDetails" roleURI="http://www.nautilus.bio/role/StockOptionPlanandStockbasedCompensationNarrativeDetails">
        <link:definition>2436420 - Disclosure - Stock Option Plan and Stock-based Compensation - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockOptionPlanandStockbasedCompensationSignificantAssumptionsDetails" roleURI="http://www.nautilus.bio/role/StockOptionPlanandStockbasedCompensationSignificantAssumptionsDetails">
        <link:definition>2437421 - Disclosure - Stock Option Plan and Stock-based Compensation - Significant Assumptions (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockOptionPlanandStockbasedCompensationStockOptionActivityDetails" roleURI="http://www.nautilus.bio/role/StockOptionPlanandStockbasedCompensationStockOptionActivityDetails">
        <link:definition>2438422 - Disclosure - Stock Option Plan and Stock-based Compensation - Stock Option Activity (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockOptionPlanandStockbasedCompensationRestrictedStockActivityDetails" roleURI="http://www.nautilus.bio/role/StockOptionPlanandStockbasedCompensationRestrictedStockActivityDetails">
        <link:definition>2439423 - Disclosure - Stock Option Plan and Stock-based Compensation - Restricted Stock Activity (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="StockOptionPlanandStockbasedCompensationStockBasedCompensationExpenseDetails" roleURI="http://www.nautilus.bio/role/StockOptionPlanandStockbasedCompensationStockBasedCompensationExpenseDetails">
        <link:definition>2440424 - Disclosure - Stock Option Plan and Stock-based Compensation - Stock Based Compensation Expense (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommitmentsandContingencies" roleURI="http://www.nautilus.bio/role/CommitmentsandContingencies">
        <link:definition>2141110 - Disclosure - Commitments and Contingencies</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommitmentsandContingenciesTables" roleURI="http://www.nautilus.bio/role/CommitmentsandContingenciesTables">
        <link:definition>2342308 - Disclosure - Commitments and Contingencies (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommitmentsandContingenciesNarrativeDetails" roleURI="http://www.nautilus.bio/role/CommitmentsandContingenciesNarrativeDetails">
        <link:definition>2443425 - Disclosure - Commitments and Contingencies - Narrative (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommitmentsandContingenciesComponentsofLeaseCostDetails" roleURI="http://www.nautilus.bio/role/CommitmentsandContingenciesComponentsofLeaseCostDetails">
        <link:definition>2444426 - Disclosure - Commitments and Contingencies - Components of Lease Cost (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommitmentsandContingenciesFutureContractualObligationsforOperatingLeaseCommitmentsDetails" roleURI="http://www.nautilus.bio/role/CommitmentsandContingenciesFutureContractualObligationsforOperatingLeaseCommitmentsDetails">
        <link:definition>2445427 - Disclosure - Commitments and Contingencies - Future Contractual Obligations for Operating Lease Commitments (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="CommitmentsandContingenciesFutureContractualObligationsforOperatingLeaseCommitmentsDetails_1" roleURI="http://www.nautilus.bio/role/CommitmentsandContingenciesFutureContractualObligationsforOperatingLeaseCommitmentsDetails_1">
        <link:definition>2445427 - Disclosure - Commitments and Contingencies - Future Contractual Obligations for Operating Lease Commitments (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BasicandDilutedNetLossperShare" roleURI="http://www.nautilus.bio/role/BasicandDilutedNetLossperShare">
        <link:definition>2146111 - Disclosure - Basic and Diluted Net Loss per Share</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BasicandDilutedNetLossperShareTables" roleURI="http://www.nautilus.bio/role/BasicandDilutedNetLossperShareTables">
        <link:definition>2347309 - Disclosure - Basic and Diluted Net Loss per Share (Tables)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BasicandDilutedNetLossperShareBasicandDilutedNetLossperShareDetails" roleURI="http://www.nautilus.bio/role/BasicandDilutedNetLossperShareBasicandDilutedNetLossperShareDetails">
        <link:definition>2448428 - Disclosure - Basic and Diluted Net Loss per Share - Basic and Diluted Net Loss per Share (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="BasicandDilutedNetLossperShareAntidilutiveSecuritiesExcludedfromComputationofEarningsperShareDetails" roleURI="http://www.nautilus.bio/role/BasicandDilutedNetLossperShareAntidilutiveSecuritiesExcludedfromComputationofEarningsperShareDetails">
        <link:definition>2449429 - Disclosure - Basic and Diluted Net Loss per Share - Antidilutive Securities Excluded from Computation of Earnings per Share (Details)</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
      <link:roleType id="SubsequentEvents" roleURI="http://www.nautilus.bio/role/SubsequentEvents">
        <link:definition>2150112 - Disclosure - Subsequent Events</link:definition>
        <link:usedOn>link:presentationLink</link:usedOn>
        <link:usedOn>link:calculationLink</link:usedOn>
        <link:usedOn>link:definitionLink</link:usedOn>
      </link:roleType>
    </xs:appinfo>
  </xs:annotation>
  <xs:element id="naut_LesseeOperatingLeaseOptionToTerminateLeaseTerm" abstract="false" name="LesseeOperatingLeaseOptionToTerminateLeaseTerm" nillable="true" xbrli:periodType="instant" substitutionGroup="xbrli:item" type="xbrli:durationItemType"/>
  <xs:element id="naut_September2021ToSeptember2031Member" abstract="true" name="September2021ToSeptember2031Member" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_DisclosureOfRedeemableConvertiblePreferredStockTextBlock" abstract="false" name="DisclosureOfRedeemableConvertiblePreferredStockTextBlock" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:textBlockItemType"/>
  <xs:element id="naut_StockConvertedValueReverseRecapitalization" abstract="false" name="StockConvertedValueReverseRecapitalization" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_A2021EmployeeStockPurchasePlanMember" abstract="true" name="A2021EmployeeStockPurchasePlanMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_AccruedFacilities" abstract="false" name="AccruedFacilities" nillable="true" xbrli:periodType="instant" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_PaymentsOfReverseRecapitalizationTransactionCosts" abstract="false" name="PaymentsOfReverseRecapitalizationTransactionCosts" nillable="true" xbrli:periodType="duration" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_OperatingLeaseNoncashAdjustment" abstract="false" name="OperatingLeaseNoncashAdjustment" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_ReverseRecapitalizationCashPaidToShareholders" abstract="false" name="ReverseRecapitalizationCashPaidToShareholders" nillable="true" xbrli:periodType="duration" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_ReverseRecapitalizationAbstract" abstract="true" name="ReverseRecapitalizationAbstract" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:stringItemType"/>
  <xs:element id="naut_ScheduleOfReverseRecapitalizationLineItems" abstract="true" name="ScheduleOfReverseRecapitalizationLineItems" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:stringItemType"/>
  <xs:element id="naut_OperatingLossCarryforwardsSubjectToExpiration" abstract="false" name="OperatingLossCarryforwardsSubjectToExpiration" nillable="true" xbrli:periodType="instant" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_StockIssuedDuringPeriodValueReverseRecapitalization" abstract="false" name="StockIssuedDuringPeriodValueReverseRecapitalization" nillable="true" xbrli:periodType="duration" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_AccruedLiabilitiesAndOtherLiabilitiesCurrent" abstract="false" name="AccruedLiabilitiesAndOtherLiabilitiesCurrent" nillable="true" xbrli:periodType="instant" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_ModificationToReduceRightOfUseAssetsAndLeaseLiability" abstract="false" name="ModificationToReduceRightOfUseAssetsAndLeaseLiability" nillable="true" xbrli:periodType="duration" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_OperatingLossCarryforwardsNotSubjectToExpiration" abstract="false" name="OperatingLossCarryforwardsNotSubjectToExpiration" nillable="true" xbrli:periodType="instant" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_AryaSciencesAcquisitionCorpIIIMember" abstract="true" name="AryaSciencesAcquisitionCorpIIIMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_WeightedAverageNumberOfSharesUnvestedRestrictedStockAndSharesSubjectToRepurchase" abstract="false" name="WeightedAverageNumberOfSharesUnvestedRestrictedStockAndSharesSubjectToRepurchase" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:sharesItemType"/>
  <xs:element id="naut_StockIssuedDuringPeriodSharesReverseRecapitalization" abstract="false" name="StockIssuedDuringPeriodSharesReverseRecapitalization" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:sharesItemType"/>
  <xs:element id="naut_October2022ToOctober2031Member" abstract="true" name="October2022ToOctober2031Member" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_DeferredTaxAssetsLeaseLiability" abstract="false" name="DeferredTaxAssetsLeaseLiability" nillable="true" xbrli:periodType="instant" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_AccruedResearchAndDevelopment" abstract="false" name="AccruedResearchAndDevelopment" nillable="true" xbrli:periodType="instant" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_ReclassificationsOfTemporaryToPermanentEquityShares" abstract="false" name="ReclassificationsOfTemporaryToPermanentEquityShares" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:sharesItemType"/>
  <xs:element id="naut_CashAcquiredThroughReverseRecapitalization" abstract="false" name="CashAcquiredThroughReverseRecapitalization" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_SeriesSeedRedeemableConvertiblePreferredStockMember" abstract="true" name="SeriesSeedRedeemableConvertiblePreferredStockMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_FurnitureFixturesAndOfficeEquipmentMember" abstract="true" name="FurnitureFixturesAndOfficeEquipmentMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_ScheduleOfCommonStockReservedForFutureIssuanceTableTextBlock" abstract="false" name="ScheduleOfCommonStockReservedForFutureIssuanceTableTextBlock" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:textBlockItemType"/>
  <xs:element id="naut_StockConvertedReverseRecapitalization" abstract="false" name="StockConvertedReverseRecapitalization" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:sharesItemType"/>
  <xs:element id="naut_ReverseRecapitalizationDisclosureTextBlock" abstract="false" name="ReverseRecapitalizationDisclosureTextBlock" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:textBlockItemType"/>
  <xs:element id="naut_A2021EquityIncentivePlanMember" abstract="true" name="A2021EquityIncentivePlanMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_ProceedsFromSaleOfStockAndReverseRecapitalizationTransaction" abstract="false" name="ProceedsFromSaleOfStockAndReverseRecapitalizationTransaction" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_ScheduleOfReverseRecapitalizationTable" abstract="true" name="ScheduleOfReverseRecapitalizationTable" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrldt:hypercubeItem" type="xbrli:stringItemType"/>
  <xs:element id="naut_RecapitalizationExchangeRatio" abstract="false" name="RecapitalizationExchangeRatio" nillable="true" xbrli:periodType="instant" substitutionGroup="xbrli:item" type="xbrli:pureItemType"/>
  <xs:element id="naut_StockIssuedDuringPeriodSharesWarrantsExercised" abstract="false" name="StockIssuedDuringPeriodSharesWarrantsExercised" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:sharesItemType"/>
  <xs:element id="naut_DeferredStockIssuanceCostsReclassifiedToEquity" abstract="false" name="DeferredStockIssuanceCostsReclassifiedToEquity" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_DeferredStockIssuanceCosts" abstract="false" name="DeferredStockIssuanceCosts" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_TemporaryEquityStockIssuedDuringPeriodSharesNewIssues" abstract="false" name="TemporaryEquityStockIssuedDuringPeriodSharesNewIssues" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="xbrli:sharesItemType"/>
  <xs:element id="naut_ProceedsFromReverseRecapitalizationTransaction" abstract="false" name="ProceedsFromReverseRecapitalizationTransaction" nillable="true" xbrli:periodType="duration" xbrli:balance="debit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_February2021ToOctober2021Member" abstract="true" name="February2021ToOctober2021Member" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_RecapitalizationExchangeRatioPerShare" abstract="false" name="RecapitalizationExchangeRatioPerShare" nillable="true" xbrli:periodType="instant" substitutionGroup="xbrli:item" type="dtr-types:perShareItemType"/>
  <xs:element id="naut_LaboratoryEquipmentMember" abstract="true" name="LaboratoryEquipmentMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_StockOptionsAndEmployeeStockPurchasePlanMember" abstract="true" name="StockOptionsAndEmployeeStockPurchasePlanMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_A2017EquityIncentivePlanMember" abstract="true" name="A2017EquityIncentivePlanMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
  <xs:element id="naut_ScheduleOfReverseRecapitalizationTableTextBlock" abstract="false" name="ScheduleOfReverseRecapitalizationTableTextBlock" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:textBlockItemType"/>
  <xs:element id="naut_TaxCreditCarryforwardOffsetByValuationAllowance" abstract="false" name="TaxCreditCarryforwardOffsetByValuationAllowance" nillable="true" xbrli:periodType="instant" xbrli:balance="credit" substitutionGroup="xbrli:item" type="xbrli:monetaryItemType"/>
  <xs:element id="naut_LongTermInvestmentsMember" abstract="true" name="LongTermInvestmentsMember" nillable="true" xbrli:periodType="duration" substitutionGroup="xbrli:item" type="dtr-types:domainItemType"/>
</xs:schema>
